Process for preparing synthesis intermediates using products of natural origin and use of the intermediates obtained

Abstract

Disclosed is a process for preparing a product of formula I: wherein the reaction is catalyzed both by thiamine or a thiamine salt and by ascorbic acid in a form which is free or salified or an organic acid salt of an alkaline metal, preferably sodium acetate, potassium tartrate, sodium succinate, or a reductone, preferably 2-hydroxypropanedial or 2,3-dihydroxycyclopent-2-ene-1-one in an organic solvent.

Claims

1. A process for preparing a product of formula I: ##STR00100## in which A represents a group selected from: COR.sub.2 COOR.sub.2a CN C(O)N Ra Ra CH(CO.sub.2Rb).sub.2 R.sub.1 represents a hydrogen atom or a linear or branched alkyl or alkylene group having at most 12 carbon atoms, or R.sub.1 represents a saturated or unsaturated cycloalkyl group having from 3 to 7 carbon atoms and optionally comprising one or more heteroatoms selected from the atoms of nitrogen, sulphur or oxygen, or R.sub.1 represents a carbocyclic or heterocyclic aryl group, each of these alkyl, alkylene, aryl or cycloalkyl groups being optionally substituted, R.sub.2 represents a linear or branched alkyl group having from 1 to carbon atoms, optionally substituted, or R.sub.2 represents a saturated or unsaturated cycloalkyl group having from 3 to 7 carbon atoms and optionally comprising one or more heteroatoms selected from the atoms of nitrogen, sulphur or oxygen, or R.sub.2 represents a carbocyclic or heterocyclic aryl group, each of these alkyl, aryl or cycloalkyl groups being optionally substituted, R.sub.2a represents a linear or branched alkyl group having from 1 to 12 carbon atoms, Ra and Ra, identical or different, are selected from linear or branched alkyl or alkoxy groups having from 1 to 12 carbon atoms, it being understood that Ra and Ra cannot simultaneously represent each a linear or branched alkoxy group having from 1 to 12 carbon atoms, Rb is selected from linear or branched alkyl groups having from 1 to 12 carbon atoms, R.sub.3 represents a hydrogen atom, or a linear or branched alkyl or alkylene group having at most 6 carbon atoms, or R.sub.3 represents a carbocyclic or heterocyclic aryl group, each of these alkyl, alkylene or aryl groups being optionally substituted, or the groups R.sub.2 and R.sub.3 are linked together to form a ring having from 5 to 7 carbon atoms, said chain optionally comprising one or more heteroatoms selected from the atoms of nitrogen, sulphur or oxygen, R.sub.4 is a hydrogen atom or is selected from optionally substituted alkyl groups, acylamido groups having from 2 to 12 carbon atoms, or carboxyl esters, wherein a product of formula II: ##STR00101## is reacted with a product of formula III ##STR00102## in the presence of both an organic compound comprising at least one ring selected from a 1,3-imidazolium, a 1,2,4-triazolium or a thiazolium and ascorbic acid in a form which is free or a salt, or a compound comprising a structure ##STR00103## in which R.sub.5 and R.sub.6 independently of one another represent a hydrogen atom, a linear or branched alkyl group having from 1 to 12 carbon atoms, or R.sub.5 and R.sub.6 are linked together to form a ring having from 3 to 7 members, said alkyl or said ring being optionally substituted by one or more heteroatoms, especially selected from O, N and S, in an organic solvent.

2. The process according to claim 1, carried out with a product of formula III in which A is COR.sub.2.

3. The process according to claim 1, in which the reaction is carried out in the presence of both an organic compound comprising at least one thiazolium ring and ascorbic acid in a form which is free or a salt, or a compound comprising a structure ##STR00104## as defined in claim 1, in an organic solvent.

4. The process according to claim 3, in which the reaction is carried out in the presence of both thiamine or a thiamine salt and ascorbic acid in a form which is free or a salt, or a compound comprising a structure ##STR00105## as defined in claim 1, in an organic solvent.

5. The process according to claim 1, wherein the one or more substituents which can be carried by the linear or branched alkyl or alkylene groups, the carbocyclic or heterocyclic aryl groups, or the cycloalkyl groups are selected from the carbocyclic or heterocyclic aryl groups, themselves optionally substituted, the free esterified or a salt carboxylic groups, the free oxo group in the form of a ketone or protected in the form of a ketal, the halogen atoms, and the alkoxy groups having from 1 to 6 carbon atoms.

6. The process according to claim 1 for preparing a product of formula Ia ##STR00106## in which R.sub.1, R.sub.3 and R.sub.4 have the meaning as indicated in claim 1 and corresponding to a product of formula I as defined in claim 1, in which A represents a COR.sub.2 group in which R.sub.2 has the meaning as indicated in claim 1, wherein a product of formula II as defined in claim 1 is reacted with a product of formula IIIa: ##STR00107## and ascorbic acid in a form which is free or a salt, in an organic solvent.

7. The process according to claim 3, wherein the substituent R.sub.1 is selected from a hydrogen atom or a linear or branched alkyl group having from 1 to 9 carbon atoms or a linear or branched alkylene group having at most 9 carbon atoms, a benzyl group or a phenyl group, R.sub.2 represents a methyl group, and R.sub.3 represents a hydrogen atom.

8. A process for preparing a compound of formula III: ##STR00108## wherein a product of formula II: ##STR00109## in which: R.sub.1 represents a linear or branched alkyl or alkylene group having at most 12 carbon atoms, or R.sub.1 represents a saturated or unsaturated cycloalkyl group having from 3 to 7 carbon atoms and optionally comprising one or more heteroatoms selected from the atoms of nitrogen, sulphur or oxygen, or R.sub.1 represents a carbocyclic or heterocyclic aryl group, each of these alkyl, alkylene, aryl or cycloalkyl groups being optionally substituted, is reacted in the presence of both a thiazolium salt, a 1,3-imidazolium salt or a 1,2,4-triazolium salt, as defined in claim 1, and ascorbic acid in a form which is free or a salt, or a compound comprising a structure ##STR00110## as defined in claim 1, in an organic solvent.

9. The process according to claim 8, in the presence of vitamin B1 and ascorbic acid in a form which is free or a salt.

10. A process for preparing a product of formula IVi ##STR00111## in which R.sub.2, R.sub.3 and R.sub.4 have the meaning indicated in claim 1, in which R.sub.1 represents a linear or branched alkyl or alkylene group having at most 12 carbon atoms, optionally substituted by a carbocyclic or heterocyclic aryl group, a CHO group, a free esterified or carboxylic salt group, an oxo group, or R.sub.1 represents a carbocyclic or heterocyclic aryl group, and R.sub.1 represents a hydrogen atom or alkyl group having more than 6 carbon atoms, wherein a product of formula IIi ##STR00112## is reacted with a product of formula IIIa: ##STR00113## as defined in claim 1 in the presence of thiamine or a thiamine salt, and ascorbic acid in a form which is free or a salt, preferably sodium ascorbate, in an organic solvent to obtain a product of formula Ii: ##STR00114## which is a product of formula Ii which is converted spontaneously into a product of formula IVi in the presence of thiamine or a thiamine salt, and ascorbic acid in a form which is free or a salt.

11. A method for the preparation of linear 1,4-dicarbonyl compounds, comprising providing a mixture comprising both an organic component comprising at least one ring selected from a 1,3-imidazolium, a 1,2,4-triazolium or a thiazolium, and ascorbic acid in a form which is free or a salt, and using said mixture to prepare said compound.

12. The method of claim 11 of a mixture comprising both an organic compound comprising at least one thiazolium ring and ascorbic acid in a form which is free or a salt.

13. The method of claim 12 in which the thiazolium is vitamin B1 or a thiamine salt.

14. The method of claim 11, in which the ascorbic acid in a form which is free or a salt is in excess in relation to the thiamine or thiamine salt is in a ratio of from 2/1 to 20/1.

15. The process according to claim 2, in which the reaction is carried out in the presence of both an organic compound comprising at least one thiazolium ring and ascorbic acid in a form which is free or a salt, or a compound comprising a structure ##STR00115## as defined in claim 1, in an organic solvent.

16. The process according to claim 2, wherein the one or more substituents which can be carried by the linear or branched alkyl or alkylene groups, the carbocyclic or heterocyclic aryl groups, or the cycloalkyl groups are selected from the carbocyclic or heterocyclic aryl groups, themselves optionally substituted, the free esterified or a salt carboxylic groups, the free oxo group in the form of a ketone or protected in the form of a ketal, the halogen atoms, and the alkoxy groups having from 1 to 6 carbon atoms.

17. The process according to claim 3, wherein the one or more substituents which can be carried by the linear or branched alkyl or alkylene groups, the carbocyclic or heterocyclic aryl groups, or the cycloalkyl groups are selected from the carbocyclic or heterocyclic aryl groups, themselves optionally substituted, the free esterified or a salt carboxylic groups, the free oxo group in the form of a ketone or protected in the form of a ketal, the halogen atoms, and the alkoxy groups having from 1 to 6 carbon atoms.

18. The process according to claim 1, wherein R.sub.4 represent a hydrogen atom.

19. The process according to claim 1, wherein the compound comprising a structure ##STR00116## is a reductone.

20. The process according to claim 19, wherein the compound the compound comprising a structure ##STR00117## is 2-hydroxypropanedial or 2,3-dihydroxycyclopent-2-en-1-one, or croconic acid.

21. The process according to claim 14, wherein the ratio is from 2/1 to 10/1.

Description

EXAMPLES

Example 1Preparation of Diketones

(1) Working Method:

(2) 10 mL of anhydrous ethanol, 33.7 mg (0.1 mmol) of thiamine hydrochloride and 119 mg (0.6 mmol) of sodium ascorbate were introduced into a flask equipped with a magnetic stirrer, a condenser and a nitrogen inlet. The mixture was stirred at room temperature for 10 minutes and then 140 mg (2.0 mmol) of 3-buten-2-one and 114 mg (1.0 mmol) heptanal were added. The mixture was stirred at reflux under a stream of dinitrogen during 24 h. The reaction medium became orange at the end of the reaction. This was removed for GC-MS analysis. The diketone produced was purified by evaporating the solvent followed by separation on a silica column (cyclohexane/AcOEt 8/2). The yield was 92%.

(3) The examples presented below were performed:

(4) TABLE-US-00002 % yield of final product 0 92 HCHO 35 74 66 0 69 74 27 0 39 73 49 0 64 31

Example 2Study of Reaction Conditions

(5) The working conditions of the reaction were studied using, as substrate, heptanal and 3-butene-2-one in the following proportions:

(6) TABLE-US-00003 m, g Mr, g/mol V, mL n, mol eq d, g/mol heptanal 0.046 114.18 0.056 0.00040 1.00 0.82 3-buten-2-one 0.056 70.09 0.065 0.00080 2.00 0.86 sodium ascorbate 0.048 198.12 0.00024 0.60 thiamine 0.013 337.23 0.00004 0.10 1,2-PrOH/iPrOH 0.100

(7) 1. Effect of Temperature

(8) The reaction was studied at three different temperatures:

(9) TABLE-US-00004 Yield Conv 70 C. 94% 68% 80 C. 92% 85% 90 C. 87% 92%

(10) The results made it possible to show that the conversion increases with temperature. The yield is best at a temperature of 80 C.

(11) 2. Method of Addition

(12) The addition method for vitamins was also studied:

(13) TABLE-US-00005 % Dura- % con- tion T C. Conditions of introduction dione version 2 h 80 C. Progressive addition of vitamins 92 85 without solvent (30 min/30 min) 2 h 90 C. Progressive addition of vitamins 87 92 without solvent (30 min/30 min) 2 h 80 C. Progressive addition of vitamins in 71 51 aqueous solution (30 min/30 min) 2 h 80 C. Progressive addition of vitamins in 79 85 iPrOH/H2O (1/1) (30 min/30 min) 2 h 80 C. Progressive addition of vitamins in 77 82 iPrOH/H2O (4/1) (30 min/30 min) 2 h 80 C. Progressive addition of vitamin B1 in 87 85 iPrOH/1,3-PrOH (1/1) (30 min/30 min) 2 h 80 C. Progressive addition of vitamin B1 in 90 84 iPrOH/1,3-PrOH (1/1) (15 min/15 min) 2 h 80 C. Progressive addition of vitamin B1 in 94 76 iPrOH/1,3-PrOH (1/1) (8 times with an interval of 15 min)

(14) It was found that the progressive addition of vitamins without solvent or in an alcohol led to a greater conversion and yield.

(15) 3. Study of the Amount of Solvent

(16) The reaction between heptanal and 3-buten-2-one was studied in different amounts of solvent (2-propanol):

(17) TABLE-US-00006 Yield Conv 0.1 mL for 0.05 mL of heptanal 90% 84% 2 0.05 eq, 80 C. 0.05 mL for 0.05 mL of heptanal 75% 86% 2 0.05 eq, 80 C. 0.05 mL for 0.05 mL of heptanal 84% 90% One pot, 80 C. 0.025 mL for 0.05 mL of heptanal 83% 83% One pot, 80 C. 0.05 mL for 0.05 mL of heptanal 72% 92% One pot, 70 C. 0.05 mL for 0.05 mL of heptanal 92% 77% One pot, 90 C.

(18) 4. Amount of Butenone

(19) The influence of the proportion of 3-buten-2-one was assessed.

(20) TABLE-US-00007 Yield Conv 2 eq 84% 90% 4 eq 72% 87%

(21) The results show that the use of four equivalents of 3-buten-2-one in relation to the heptanal led to a lower yield of 1,4-diketone compared to the use of 2 equivalents.

Example 3Acyloin Condensation of Heptanol with Vitamins

(22) ##STR00084##

(23) Working Method:

(24) Heptanal (0.1 mL, 0.72 mmol), 3-buten-2-one (0.03 mL, 0.36 mmol), sodium ascorbate (0.086 g, 0.43 mmol), and thiamine (0.024 g, 0.07 mmol) were added to the mixture of iPrOH/1,2-propanediol (1/1) (0.09 mL) at ambient temperature. The reaction mixture was then stirred for 3 hours at 80 C. under inert atmosphere. At the end of 3 hours the reaction crude was analysed by GC/GMS, the desired product having been obtained with a yield of 63% with 57% conversion (in total 36% of product in the reaction crude).

Example 4Preparation of Cyclopentenones from 1,4-Diketones

(25) Working Method:

(26) 10 mL of anhydrous ethanol, 33.7 mg (0.1 mmol) of thiamine hydrochloride and 119 mg (0.6 mmol) of sodium ascorbate were introduced into a flask equipped with a magnetic stirrer, a condenser and a nitrogen inlet. The mixture was stirred at room temperature for 10 minutes and then 140 mg (2.0 mmol) of 3-buten-2-one and 112 mg (1.0 mmol) of hepten-2-al were added. The mixture was stirred at reflux under a stream of dinitrogen during 24 h. The development of the reaction medium was monitored by GC-MS analysis. The cyclopentenone obtained was purified by evaporation of the solvent followed by separation on a silica column (toluene/AcOEt 9/1). The yield was 51%.

(27) Using the working method described above, the following products were obtained:

(28) TABLE-US-00008 % yield of cyclopentenone 0 51 49 19 89