EP3774756A1 - Process for the manufacture of chroman-6-ols with short side chains - Google Patents

Process for the manufacture of chroman-6-ols with short side chains

Info

Publication number
EP3774756A1
EP3774756A1 EP19713808.4A EP19713808A EP3774756A1 EP 3774756 A1 EP3774756 A1 EP 3774756A1 EP 19713808 A EP19713808 A EP 19713808A EP 3774756 A1 EP3774756 A1 EP 3774756A1
Authority
EP
European Patent Office
Prior art keywords
range
solvents
formula
process according
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19713808.4A
Other languages
German (de)
French (fr)
Inventor
Marcel Joray
Thomas Netscher
René Tobias STEMMLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of EP3774756A1 publication Critical patent/EP3774756A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • the present invention is directed to a process for the manufacture of a compound of formula (III),
  • R 1 is Ci- 5 -alkyl
  • R 2 is either H or Ci- 2 -alkyl
  • R 4 is either H or Ci- 4 -alkoxy or Ci- 4 -alkyl
  • R 3 and R 5 are independently from each other either H or Ci- 4 -alkyl, and the first of the two solvents is water,
  • the second of the two solvents is selected from aliphatic Cs-s-hydrocarbons, cycloaliphatic Cs-s-hydrocarbons, dialkyl ethers and methyl-substituted benzenes and any mixture thereof.
  • reaction can be also carried out with isoprene according to various publications with yields in the range of 53-62% (see R. H. Cichewicz, V. A. Kenyon, S. Whitman, N. M. Morales, J. F. Arguello, T. R. Holman, P. Crews:“Redox Inactivation of Human 15-Lipoxygenase by Marine-Derived Meroditerpenes and Synthetic Chromanes: Archetypes for a Unique Class of Selective and Recyclable Inhibitors”, J. Am. Chem. Soc. 2004, 126, 14910-14920; G. P. Kalena, A. Jain, A.
  • Banerji «Amberlyst 15 Catalyzed Prenylation of Phenols: One-Step Synthesis of Benzopyrans.”, Molecules 1997, 2, 100-105 (using Amberlyst 15 in THF/heptane, 65-70° C, 2.5 h, 61%); V. K. Ahluwalia, K. K. Arora, R. S. Jolly:“Acid-catalysed condensation of isoprene with phenols. Formation of 2,2-dimethylchromans.”, J. Chem. Soc., Perkin Trans. 1 1982, 335-338 (H3PO4); F. Bigi, S. Carloni, R. Maggi, C. Muchetti, M.
  • prenyl acetate has been shown to react with HQ catalyzed by ln(OTf) 3 , a salt of the rare earth metal indium, (see V. Vece, J. Ricci, S. Poulain- Martini, P. Nava, Y. Carissan, S. Humbel, E. Duhach:“ I n ( 111 ) - Cat a lysed Tandem C-C and C-0 Bond Formation between Phenols and Allylic Acetates”, Eur. J. Org. Chem. 2010, 6239-6248.).
  • dichloromethane a halogenated solvent, had to be used.
  • Step 1 MeSOsH as solvent; 50 mol-% of P 2 Os, yield 91% (see F. Camps, J. Coll, A. Messeguer, M. A. Pericas, S. Spainrt, W. S. Bowers, D. M. Soderlund:“An Improved Procedure for the Preparation of 2,2-Dimethyl-4-chromanones.”, Synthesis 1980, 725-727.).
  • Step 2) LiAlH 4 , Et 2 0, yield 87% (see P. Anastasis, P. E. Brown:“Analogues of antijuvenile hormones.”, J. Chem. Soc., Perkin Trans. 1 1982, 2013-2018.).
  • the total yield is 79% over the two steps.
  • R 1 is Ci- 5 -alkyl
  • R 2 is either H or Ci- 2 -alkyl
  • R 4 is either H or Ci- 4 -alkoxy or Ci- 4 -alkyl
  • R 3 and R 5 are independently from each other either H or Ci- 4 -alkyl
  • the first of the two solvents is water
  • both the used acid catalyst and excess of compound of formula (I) are reusable, simply by separating the product phase from the phase containing catalyst and excess of compound of formula (I).
  • OR is preferably OH or acetate.
  • R 1 is preferably methyl.
  • R 2 is preferably H or methyl; more preferably R 2 is methyl.
  • R 4 is preferably either H or methoxy or methyl, more preferably R 4 is H or methoxy.
  • R 3 and R 5 are preferably independently from each other either H or methyl.
  • alkyl and“alkoxy” in the context of the present invention encompass linear alkyl and branched alkyl, and linear alkoxy and branched alkoxy, respectively.
  • Fig. 2-5 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (III- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and 2-methylbut-3- en-2-ol (compound of formula (IIA-1 )).
  • Fig. 3 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (MI- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and isoprene
  • FIG. 4 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (III- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and a prenyl derivative (compound of formula (IIC-1 )).
  • Fig. 5 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (III- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and prenol
  • the molar ratio of the compound of formula (I) to the compound of formula (IIA), (MB) or (IIC) is in the range of 6.0: 1 to 1.1 :1 , more preferably in the range of 4.0:1 to 1.3: 1 , even more preferably in the range of from 3.0: 1 to 1.5:1 , most preferably in the range of 2.5:1 to 1 .7:1 .
  • all embodiments of the present invention with regard to the starting materials and the preferences as given above are realized.
  • aliphatic Cs-s-hydrocarbons are hexane and heptane.
  • hexane encompasses n-hexane, as well as any mixture of the isomers of hexane. The same applies for heptane.
  • a preferred example of a cycloaliphatic Cs-s-hydrocarbon is cyclohexane.
  • the alkyl groups in the dialkyl ethers may be identical or different, preferably they are different.
  • the alkyl groups are aliphatic linear Ci- 5 -alkyl groups or branched C alkyl groups.
  • a preferred example of a dialkyl ether is methyl tert- butyl ether.
  • methyl-substituted benzenes are ortho-xylene, meta-xylene, para-xylene, mesitylene, pseudocumene, and toluene.
  • the second solvent is hexane, cyclohexane, heptane, ortho-xylene, meta-xylene, para-xylene, mesitylene, pseudocumene, methyl tert- butyl ether, or toluene, and any mixture thereof.
  • the second solvent is hexane, cyclohexane, heptane, ortho-xylene, meta-xylene, para-xylene, mesitylene, pseudocumene, methyl tert- butyl ether, or toluene.
  • the first of the two solvents is water and the second of the two solvents is selected from either mesitylene, pseudocumene, ortho-xylene, meta-xylene, para-xylene or toluene, more preferably the first of the two solvents is water and the second of the two solvents is selected from either ortho-xylene, meta-xylene, para-xylene or toluene, most preferably the first of the two solvents is water and the second of the two solvents is toluene.
  • the volume ratio of the first solvent to the second solvent during the reaction is in the range of 1 :4 to 4:1 , more preferably the volume ratio of the first solvent to the second solvent is in the range of 1 :3 to 3:1 , most preferably the volume ratio of the first solvent to the second solvent is in the range of 1 :2 to 2:1 .
  • the total amount of the two solvents is in the range of 1 to 8 kg, preferably in the range of 2 to 6 kg, more preferably in the range of 2.5 to 5.5 kg, per kg of the compound of formula (I).
  • all embodiments of the present invention with regard to the solvent and the preferences as given above are realized.
  • the water may be added as such to the reaction mixture or as an aqueous solution of an acid catalyst with the preferences as disclosed below, i.e. a mixture of water and the acid catalyst may be used.
  • the preferred amounts of water given above also encompass the water contained in the aqueous solution of the acid catalyst.
  • Suitable acid catalysts are Bronsted acids and Lewis acids and any mixture thereof.
  • Bronsted acids are sulfuric acid, phosphoric acid, acidic ion-exchange resins (e.g. Amberlyst 15), acidic clays (e.g. Montmorillonite K-10), zeolites (e.g. HSZ-360), hydrochloric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, bis(perfluoroalkyl- sulfonyl)methanes (R’S0 2 )(R”S0 2 )CH 2 wherein R’ and R” each signify independently from each other a perfluoroalkyl group of the formula C n F 2n+i where n is an integer from 1 to 10, tris(perfluorosulfonyl)methane
  • pentafluorophenyl group (-C 6 F 5 ) and R” and R’” each signify an identical perfluoroalkyl group of the above formula C n F 2n+i , methanetrisulfonic acid, and bis(trifluormethylsulfonyl)imide, and any mixture thereof, whereby the use of single catalysts is preferred.
  • Lewis acids are Sc(OTf) 3 , Sc(NTf 2 ) 3 , ScCl 3 , Yb(OTf) 3 , YbCl 3 , Cu(OTf) 2 , FeCl 2 , Fe(OTf) 2 , ZnCl 2 , Zn(OTf) 2 , Zn(NTf 2 ) 3 , YCl 3 , Y(OTf) 3 , lnCl 3 , lnBr 3 , ln(OTf) 3 , ln(NTf 2 ) 3 , La(OTf) 3 , Ce(OTf) 3 , Sm(OTf) 3 , Gd(OTf) 3 , Bi(OTf) 3 in the absence or presence of 2,2-bipyridine and any mixture thereof, whereby the use of single catalysts is preferred.
  • the acid catalyst is sulfuric acid, hydrochloric acid, formic acid, Amberlyst 15, trifluoroacetic acid, or phosphoric acid or their aqueous
  • the acid catalyst is sulfuric acid, hydrochloric acid or Amberlyst 15, most preferably the acid catalyst is sulfuric acid. Mixtures of these catalysts may also be used.
  • the acid catalyst is sulfuric acid and the concentration of said sulfuric acid is in the range of from 0.1 to 10 mol/L, preferably wherein the concentration of said sulfuric acid is in the range of 0.4 to 4.0 mol/L.
  • the amount of the acid catalyst is in the range of 0.01 to 10 mol equivalents, more preferably in the range of 0.05 to 5 mol equivalents, most preferably in the range of 0.1 to 1 mol equivalents, relative to the amount of compound of formula (IIA), (MB), or (IIC).
  • the reaction is preferably carried out at a temperature in the range of 50 to 140°C, more preferably in the range of 60 to 120°C, even more preferably in the range of 70 to 100°C, most preferably in the range of 75 to 90° C.
  • the reaction is preferably carried out at a pressure in the range of 0.5 to 20 bar (absolute), more preferably at a pressure in the range of 0.7 to 10 bar (absolute), most preferably at a pressure in the range of 0.8 to 5 bar (absolute).
  • Example 1 Synthesis of 2.2-dimethylchroman-6-ol starting from 1 .4- hydroquinone and 2-methylbut-3-en-2-ol
  • the combined organic phases were washed with 100 ml. of brine (10 % aqueous NaCl solution), subsequently dried over sodium sulfate, filtered and evaporated at 40° C/200-10 mbar.
  • the heterogeneous, crude material (31 .5 g) was digested in 50 ml. of heptane/ethyl acetate (90/10 w/w) and filtered.
  • the filter cake (mostly HQ) was washed with 50 ml. of heptane/ethyl acetate (90/10 w/w).
  • the filtrate was concentrated in vacuo (40°C/200-10 mbar), furnishing crude product (14.4 g).
  • This material was purified by column chromatography; eluent gradient heptane to heptane/EtOAc 80:20 (w/w). The pure fractions were combined and concentrated in vacuo (40° C/200-10 mbar). The residue was taken up in 30 ml. of dichloromethane and subsequently evaporated again to dryness (40 ° C/200-0.1 mbar), furnishing 5.6 g of DMC as off-white crystals (31.4 mmol, 98.5% purity by qNMR, 37% yield).
  • the toluene solution was then concentrated in a rotary evaporator to furnish 29.60 g of crude DMC as beige oil (assay 75.4% by ql_C, a chemical yield of 78.7% relative to MBE).
  • the crude material was purified in a distillation apparatus equipped with a Vigreux column (20 cm) at 0.3 mbar and 125°C (internal temperature), furnishing one fraction: 22.40 g of DMC (assay 97.0% by quant. LC, 121.9 mmol, 76.5% isolated yield), mp. 74.5-75°C.
  • Example 3 Synthesis of 2.2-dimethylchroman-6-ol starting from 1.4- hydroquinone and 2-methylbut-3-en-2-ol: Recycling of catalyst and 1 .4- hydroquinone phase
  • a 1 .5 L 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 651 g aqueous phase from the previous run (carried out on the same scale as the present run; containing hydroquinone, approx. 3 mol equiv., -1 .17 mol, and sulfuric acid, -0.4 M, 0.78 mol, 0.5 mol equiv.
  • Example 6 Synthesis of 2.2-dimethylchroman-6-ol starting from 1 .4- hydroquinone and 2-methylbut-3-en-2-ol in the presence of Amberlyst 15 as acid catalyst A 200 ml. 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 8.0 g of 1 ,4-hydroquinone (72.2 mmol, 99.5%, 1 .9 mol equiv.) and 2-methyl-3-buten-2-ol (4.0 ml_, 39 mmol, 1 .0 mol equiv.), which were then suspended in 50 ml.
  • Example 14 Synthesis of 2.2-dimethylchroman-6-ol (“DM- chromanol”) starting from 1 .4-hydroquinone (“HQ”) and 2-methylbut-3-en-2-ol (“MBE”) according to the conditions disclosed in US 4,217,285 , i.e. in the presence of ZnCb, silica-alumina and concentrated hydrochloric acid
  • DM- chromanol 2.2-dimethylchroman-6-ol
  • HQ 1 .4-hydroquinone
  • MBE 2-methylbut-3-en-2-ol

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention is directed to a process for the manufacture of a compound of formula (III), comprising the step of reacting a compound of formula (I) with a compound of formula (IIA), (IIB) or (IIC) in the presence of an acid catalyst and in a mixture of two solvents, wherein OR is OH, acetate, methanoate, propionate, butyrate or benzoate, A is CH2, R1 is C1-5-alkyl, R2 is either H or C1-2-alkyl, R4 is either H or C1-4-alkoxy or C1-4-alkyl, R3 and R5 are independently from each other either H or C1-4-alkyl, and the first of the two solvents is water, and the second of the two solvents is selected from aliphatic C5-8-hydrocarbons, cycloaliphatic C5-8-hydrocarbons, dialkyl ethers and methyl-substituted benzenes and any mixture thereof.

Description

Process for the manufacture of chroman-6-ols with short side chains
Summary The present invention is directed to a process for the manufacture of a compound of formula (III),
comprising the step of reacting a compound of formula (I) with a compound of formula (IIA), (MB) or (IIC) in the presence of an acid catalyst and in a mixture of two solvents,
(I) (HA) (MB) (I IC) wherein OR is OH, acetate, methanoate, propionate, butyrate or benzoate, A is CH2,
R1 is Ci-5-alkyl,
R2 is either H or Ci-2-alkyl,
R4 is either H or Ci-4-alkoxy or Ci-4-alkyl,
R3 and R5 are independently from each other either H or Ci-4-alkyl, and the first of the two solvents is water,
and the second of the two solvents is selected from aliphatic Cs-s-hydrocarbons, cycloaliphatic Cs-s-hydrocarbons, dialkyl ethers and methyl-substituted benzenes and any mixture thereof.
l Background of the invention
Q. Wang, X. She, X. Ren, J. Ma, X. Pan described the condensation of 2-methylbut- 3-en-2-ol with 1 ,4-hydroguinone (“HQ”) to 2,2-dimethyl-chroman-6-ol (“DMC”; compound of formula (111-1 )) in 80% formic acid with a yield of 56% (“The First Asymmetric Total Synthesis of Several 3,4-Dihydroxy-2,2-Dimethyl-Chroman Derivatives.”, Tetrahedron: Asymmetry 2004, 15 (1 ), 29-34.).
The reaction has also been described with trifluoroacetic acid as reaction medium (33% yield of DMC) (see F. M. D. Ismail, M. J. Hilton, M. Stefinovic:“Versatile Synthesis of Benzopyrans via Ortho-Claisen Rearrangement of Allyl Ethers.”, Tetrahedron Lett. 1992, 33, 3795-3796.).
Alternatively, the reaction can be also carried out with isoprene according to various publications with yields in the range of 53-62% (see R. H. Cichewicz, V. A. Kenyon, S. Whitman, N. M. Morales, J. F. Arguello, T. R. Holman, P. Crews:“Redox Inactivation of Human 15-Lipoxygenase by Marine-Derived Meroditerpenes and Synthetic Chromanes: Archetypes for a Unique Class of Selective and Recyclable Inhibitors”, J. Am. Chem. Soc. 2004, 126, 14910-14920; G. P. Kalena, A. Jain, A. Banerji: «Amberlyst 15 Catalyzed Prenylation of Phenols: One-Step Synthesis of Benzopyrans.”, Molecules 1997, 2, 100-105 (using Amberlyst 15 in THF/heptane, 65-70° C, 2.5 h, 61%); V. K. Ahluwalia, K. K. Arora, R. S. Jolly:“Acid-catalysed condensation of isoprene with phenols. Formation of 2,2-dimethylchromans.”, J. Chem. Soc., Perkin Trans. 1 1982, 335-338 (H3PO4); F. Bigi, S. Carloni, R. Maggi, C. Muchetti, M. Rastelli, G. Sartori:“Reaction between Phenols and Isoprene under Zeolite Catalysis. Highly Selective Synthesis of Chromans and o-lsopentenyl- phenols.”, Synthesis 1998, 301 -304 (zeolite HSZ-360, autoclave, 120°C, 5 h, 50% yield); R. Nast, M. Dahm, K. Ley (Bayer):“Polyurethane Foams Stabilized with 6- Hydroxy Chromans”, DE 194 52 12 (H3PO4 in xylene/petrol ether, 62% yield). Furthermore, prenyl acetate has been shown to react with HQ catalyzed by ln(OTf)3, a salt of the rare earth metal indium, (see V. Vece, J. Ricci, S. Poulain- Martini, P. Nava, Y. Carissan, S. Humbel, E. Duhach:“ I n ( 111 ) - Cat a lysed Tandem C-C and C-0 Bond Formation between Phenols and Allylic Acetates”, Eur. J. Org. Chem. 2010, 6239-6248.). Here, however, dichloromethane, a halogenated solvent, had to be used. Furthermore, 10 mol equiv. phenolic compound relative to 1 mol equiv. allyl acetate have to be used. Though a yield of 94% is given, it will be costly to find a process for recycling the excess of HQ. Therefore, the yield relative to HQ is <10%. A further disadvantage is that acetate is a stoichiometric by-product versus
H20 in case of 2-methyl-3-buten-2-ol (“MBE”) or none in case of isoprene.
A two-step synthesis of the compound of formula (III -2) has already been described in the literature and the reaction scheme is shown in Fig. 1 .
Step 1 ): MeSOsH as solvent; 50 mol-% of P2Os, yield 91% (see F. Camps, J. Coll, A. Messeguer, M. A. Pericas, S. Ricart, W. S. Bowers, D. M. Soderlund:“An Improved Procedure for the Preparation of 2,2-Dimethyl-4-chromanones.”, Synthesis 1980, 725-727.).
Step 2): LiAlH4, Et20, yield 87% (see P. Anastasis, P. E. Brown:“Analogues of antijuvenile hormones.”, J. Chem. Soc., Perkin Trans. 1 1982, 2013-2018.).
The total yield is 79% over the two steps.
The present yields provided by the literature known processes are, however, not high enough for a sustainable industrial process. Thus, there was a need to provide a sustainable industrial process for the manufacture of compounds of formula (III) with a good yield based on the compound of formula (I), whereby the use of halogenated solvents is avoided. Detailed description of the invention
Thus, this need is fulfilled by the present invention, which is directed to a process for the manufacture of a compound of formula (III),
comprising the step of reacting a compound of formula (I) with a compound of formula (IIA), (MB) or (IIC) in the presence of an acid catalyst and in a mixture of two solvents,
(I) (HA) (MB) (IIC) wherein OR is OH, acetate, methanoate, propionate, butyrate or benzoate, A is CH2,
R1 is Ci-5-alkyl,
R2 is either H or Ci-2-alkyl,
R4 is either H or Ci-4-alkoxy or Ci-4-alkyl,
R3 and R5 are independently from each other either H or Ci-4-alkyl, and
the first of the two solvents is water,
and the second of the two solvents is selected from aliphatic Cs-s-hydrocarbons, cycloaliphatic Cs-s-hydrocarbons, dialkyl ethers and methyl-substituted benzenes and any mixture thereof. Hereby the use of halogenated solvents is avoided. Advantageously, both the used acid catalyst and excess of compound of formula (I) are reusable, simply by separating the product phase from the phase containing catalyst and excess of compound of formula (I).
Starting material and product
OR is preferably OH or acetate. R1 is preferably methyl.
R2 is preferably H or methyl; more preferably R2 is methyl.
R4 is preferably either H or methoxy or methyl, more preferably R4 is H or methoxy.
R3 and R5 are preferably independently from each other either H or methyl.
“alkyl” and“alkoxy” in the context of the present invention encompass linear alkyl and branched alkyl, and linear alkoxy and branched alkoxy, respectively.
The most preferred compounds used as starting materials and the most preferred compounds obtained as products by the process of the present invention are shown in Fig. 2-5. Fig. 2 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (III- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and 2-methylbut-3- en-2-ol (compound of formula (IIA-1 )).
Fig. 3 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (MI- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and isoprene
(compound of formula (IIB-1 )). Fig. 4 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (III- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and a prenyl derivative (compound of formula (IIC-1 )). Fig. 5 shows the synthesis of 2,2-dimethylchroman-6-ol (compound of formula (III- 1 )) starting from 1 ,4-hydroquinone (compound of formula (1-1 )) and prenol
(compound of formula (IIC-2)).
In a preferred embodiment of the present invention the molar ratio of the compound of formula (I) to the compound of formula (IIA), (MB) or (IIC) is in the range of 6.0: 1 to 1.1 :1 , more preferably in the range of 4.0:1 to 1.3: 1 , even more preferably in the range of from 3.0: 1 to 1.5:1 , most preferably in the range of 2.5:1 to 1 .7:1 . In a further embodiment of the present invention all embodiments of the present invention with regard to the starting materials and the preferences as given above are realized.
Solvent mixture
Preferred examples of aliphatic Cs-s-hydrocarbons are hexane and heptane. The term“hexane” encompasses n-hexane, as well as any mixture of the isomers of hexane. The same applies for heptane.
A preferred example of a cycloaliphatic Cs-s-hydrocarbon is cyclohexane.
The alkyl groups in the dialkyl ethers may be identical or different, preferably they are different. Preferably the alkyl groups are aliphatic linear Ci-5-alkyl groups or branched C alkyl groups. A preferred example of a dialkyl ether is methyl tert- butyl ether.
Preferred examples of methyl-substituted benzenes are ortho-xylene, meta-xylene, para-xylene, mesitylene, pseudocumene, and toluene. Preferably the second solvent is hexane, cyclohexane, heptane, ortho-xylene, meta-xylene, para-xylene, mesitylene, pseudocumene, methyl tert- butyl ether, or toluene, and any mixture thereof. More preferably the second solvent is hexane, cyclohexane, heptane, ortho-xylene, meta-xylene, para-xylene, mesitylene, pseudocumene, methyl tert- butyl ether, or toluene.
In a preferred embodiment of the present invention the first of the two solvents is water and the second of the two solvents is selected from either mesitylene, pseudocumene, ortho-xylene, meta-xylene, para-xylene or toluene, more preferably the first of the two solvents is water and the second of the two solvents is selected from either ortho-xylene, meta-xylene, para-xylene or toluene, most preferably the first of the two solvents is water and the second of the two solvents is toluene. In a preferred embodiment of the present invention the volume ratio of the first solvent to the second solvent during the reaction is in the range of 1 :4 to 4:1 , more preferably the volume ratio of the first solvent to the second solvent is in the range of 1 :3 to 3:1 , most preferably the volume ratio of the first solvent to the second solvent is in the range of 1 :2 to 2:1 .
In another embodiment of the present invention the total amount of the two solvents is in the range of 1 to 8 kg, preferably in the range of 2 to 6 kg, more preferably in the range of 2.5 to 5.5 kg, per kg of the compound of formula (I). In a further embodiment of the present invention all embodiments of the present invention with regard to the solvent and the preferences as given above are realized.
The water may be added as such to the reaction mixture or as an aqueous solution of an acid catalyst with the preferences as disclosed below, i.e. a mixture of water and the acid catalyst may be used. In a preferred embodiment of the present invention the preferred amounts of water given above also encompass the water contained in the aqueous solution of the acid catalyst. Acid catalyst
Examples of suitable acid catalysts are Bronsted acids and Lewis acids and any mixture thereof.
Examples of Bronsted acids are sulfuric acid, phosphoric acid, acidic ion-exchange resins (e.g. Amberlyst 15), acidic clays (e.g. Montmorillonite K-10), zeolites (e.g. HSZ-360), hydrochloric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, bis(perfluoroalkyl- sulfonyl)methanes (R’S02)(R”S02)CH2 wherein R’ and R” each signify independently from each other a perfluoroalkyl group of the formula CnF2n+i where n is an integer from 1 to 10, tris(perfluorosulfonyl)methanes (R’S02)(R”S02)(R”’S02)CH, wherein R’, R” and R’” each signify independently from each other a perfluoroalkyl group of the formula CnF2n+i where n is an integer from 1 to 10, and whereby at least two of R’, R” and R’” are identical perfluoroalkyl groups, or R’ signifies the
pentafluorophenyl group (-C6F5) and R” and R’” each signify an identical perfluoroalkyl group of the above formula CnF2n+i, methanetrisulfonic acid, and bis(trifluormethylsulfonyl)imide, and any mixture thereof, whereby the use of single catalysts is preferred.
Examples of Lewis acids are Sc(OTf)3, Sc(NTf2)3, ScCl3, Yb(OTf)3, YbCl3, Cu(OTf)2, FeCl2, Fe(OTf)2, ZnCl2, Zn(OTf)2, Zn(NTf2)3, YCl3, Y(OTf)3, lnCl3, lnBr3, ln(OTf)3, ln(NTf2)3, La(OTf)3, Ce(OTf)3, Sm(OTf)3, Gd(OTf)3, Bi(OTf)3 in the absence or presence of 2,2-bipyridine and any mixture thereof, whereby the use of single catalysts is preferred.
Preferably the acid catalyst is sulfuric acid, hydrochloric acid, formic acid, Amberlyst 15, trifluoroacetic acid, or phosphoric acid or their aqueous
solutions/suspensions, more preferably the acid catalyst is sulfuric acid, hydrochloric acid or Amberlyst 15, most preferably the acid catalyst is sulfuric acid. Mixtures of these catalysts may also be used. In a preferred embodiment of the present invention the acid catalyst is sulfuric acid and the concentration of said sulfuric acid is in the range of from 0.1 to 10 mol/L, preferably wherein the concentration of said sulfuric acid is in the range of 0.4 to 4.0 mol/L.
In a further preferred embodiment of the present invention the amount of the acid catalyst is in the range of 0.01 to 10 mol equivalents, more preferably in the range of 0.05 to 5 mol equivalents, most preferably in the range of 0.1 to 1 mol equivalents, relative to the amount of compound of formula (IIA), (MB), or (IIC).
In a further embodiment of the present invention all embodiments of the present invention with regard to the catalyst and the preferences as given above are realized. Reaction conditions
The reaction is preferably carried out at a temperature in the range of 50 to 140°C, more preferably in the range of 60 to 120°C, even more preferably in the range of 70 to 100°C, most preferably in the range of 75 to 90° C.
The reaction is preferably carried out at a pressure in the range of 0.5 to 20 bar (absolute), more preferably at a pressure in the range of 0.7 to 10 bar (absolute), most preferably at a pressure in the range of 0.8 to 5 bar (absolute). In the process according to the present invention the acid catalyst is recyclable (= re-usable) which is a further advantage of the present invention.
In a further embodiment of the present invention all embodiments of the present invention with regard to the reaction conditions and the preferences as given above are realized.
In the most preferred embodiments of the present invention all embodiments of the present invention with regard to the starting materials, the solvent, the catalyst and the reaction conditions including the preferences as given above are realized.
The invention is now further illustrated in the following non-limiting examples.
Examples
Comparison example:
Example 1 : Synthesis of 2.2-dimethylchroman-6-ol starting from 1 .4- hydroquinone and 2-methylbut-3-en-2-ol
A 500-mL flask equipped with reflux condenser, magnetic stirrer and argon supply was charged with 18.6 g of hydroquinone (167 mmol, 99%, 2.0 mol equiv.) and dissolved in 250 g of formic acid (5.4 mol, 65 mol equiv.) and 70 g of water at room temperature.
7.2 g of 2-methylbut-3-en-2-ol (83 mmol, 99%, 1 .0 mol equiv.) was added and heated to reflux for 4 h, during which the colorless solution darkened slowly. The reaction mixture was then cooled and poured into 1200 g of iced water and neutralized to pH 7 by cautious addition (exothermicity, C02 evolution) of 240 g of sodium carbonate (2.25 mol, technical grade) and subsequently 1 12 g of sodium bicarbonate (1 .27 mol, technical grade) in small portions. The light brown, turbid solution was extracted with 250 ml. of ethyl acetate and subsequently 100 ml. of ethyl acetate. The combined organic phases were washed with 100 ml. of brine (10 % aqueous NaCl solution), subsequently dried over sodium sulfate, filtered and evaporated at 40° C/200-10 mbar. The heterogeneous, crude material (31 .5 g) was digested in 50 ml. of heptane/ethyl acetate (90/10 w/w) and filtered. The filter cake (mostly HQ) was washed with 50 ml. of heptane/ethyl acetate (90/10 w/w). The filtrate was concentrated in vacuo (40°C/200-10 mbar), furnishing crude product (14.4 g). This material was purified by column chromatography; eluent gradient heptane to heptane/EtOAc 80:20 (w/w). The pure fractions were combined and concentrated in vacuo (40° C/200-10 mbar). The residue was taken up in 30 ml. of dichloromethane and subsequently evaporated again to dryness (40 ° C/200-0.1 mbar), furnishing 5.6 g of DMC as off-white crystals (31.4 mmol, 98.5% purity by qNMR, 37% yield).
Examples according to the present invention: Examples 2-13
Example 2: Synthesis of 2.2-dimethylchroman-6-ol starting from 1.4- hydroquinone and 2-methylbut-3-en-2-ol
A 200 ml. 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 35.1 g of hydroquinone (319 mmol, 99.5%, 2.0 mol equiv.) which was suspended in 77.7 g of sulfuric acid (0.4 M, 0.17 mol equiv.) and 43.5 g of toluene (50 ml_). The two-phase reaction mixture was heated to reflux (85 °C internal temperature) upon which all hydroquinone dissolved in the aqueous phase. Then, 14.0 g of 2-methyl-3-buten-2-ol (“MBE”) (159 mmol, 98.0%, 1 .0 mol equiv.) was added to the refluxing reaction mixture over 2 h. After complete addition, the reaction was stirred for additional 3 h at 85 °C (internal temperature). While still warm, the reaction mixture was then transferred to a separating funnel and the colorless phases were separated. The aqueous phase (containing sulfuric acid and excess HQ) was retained for the next reaction cycle. The organic phase was washed with deionized water (2 x 25 ml_). The water phase was then back-extracted with toluene, a total of 45 g of toluene (2x 26 ml_). The toluene solution was then concentrated in a rotary evaporator to furnish 29.60 g of crude DMC as beige oil (assay 75.4% by ql_C, a chemical yield of 78.7% relative to MBE). The crude material was purified in a distillation apparatus equipped with a Vigreux column (20 cm) at 0.3 mbar and 125°C (internal temperature), furnishing one fraction: 22.40 g of DMC (assay 97.0% by quant. LC, 121.9 mmol, 76.5% isolated yield), mp. 74.5-75°C.
Example 3: Synthesis of 2.2-dimethylchroman-6-ol starting from 1.4- hydroquinone and 2-methylbut-3-en-2-ol: Recycling of catalyst and 1 .4- hydroquinone phase
A 1 .5 L 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 651 g aqueous phase from the previous run (carried out on the same scale as the present run; containing hydroquinone, approx. 3 mol equiv., -1 .17 mol, and sulfuric acid, -0.4 M, 0.78 mol, 0.5 mol equiv. and -3 mol% product), and additional, fresh hydroquinone (43.0 g, 390 mmol, 99.5%, 1 .0 mol equiv.) and 2-methyl-3-buten-2-ol (33.7 g, 387 mmol, 99.0%, 1 .0 mol equiv.) dissolved in toluene (500 ml_). The two-phase reaction mixture was heated to reflux (85 °C internal temperature) for 4 h. While still warm, the reaction mixture was then transferred to a separating funnel and the colorless phases were separated. The aqueous phase (approx. 650 g), containing sulfuric acid and excess HQ) was retained for the next reaction cycle. The organic phase was washed with water (2 x 250 ml_). The water phase was then back-extracted with toluene (250 ml_). The toluene solution was then concentrated in a rotary evaporator to furnish crude 2,2-dimethylchroman-6-ol as beige oil (93.88 g, 64.8% purity by quant. LC, 88% yield). Example 4: Synthesis of 2.2-dimethylchroman-6-ol starting from 1 .4- hydroquinone and prenol (see Fig. 5)
A 350 ml. 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 17.5 g of 1 ,4-hydroquinone (159 mmol, 99.5%, 4.0 mol equiv.) and prenol (3.45 g, 39.7 mmol, 99%, 1 .0 mol equiv.), which were then suspended in 50 ml. of sulfuric acid (0.4 M, 0.5 mol equiv.) and 43.5 g of toluene (50 ml_). The two-phase reaction mixture was heated to reflux (84°C internal temperature) for 4.5 h. While still warm, the reaction mixture was then transferred to a separating funnel and the colorless phases were separated. The warm aqueous phase was extracted with toluene (2x 25 ml.) and the combined organic phases were washed with water (2x 25 ml_), dried over Na2S04 and concentrated in vacuo (40° C/50-20 mbar), furnishing crude DMC as beige oil (7.0 g, 76.3% purity by quant. LC, 76% yield). Example 5: Synthesis of 2.2-dimethylchroman-6-ol starting from 1 .4- hydroquinone and isoprene (see Fig. 3)
A 200 mL 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 17.8 g of 1 ,4-hydroquinone (161 mmol, 99.5%, 4.0 mol equiv.) and isoprene (2.75 g, 40.4 mmol, 1 .0 mol equiv.), which were then suspended in 50 ml. of sulfuric acid (0.4 M, 0.5 mol equiv.) and 43.5 g of toluene (50 ml_). The two-phase reaction mixture was heated to reflux (internal temperature rises slowly to 82°C during reflux; oil bath at 100°C) for 26 h. While still warm, the reaction mixture was then transferred to a separating funnel and the colorless phases were separated. The warm aqueous phase was extracted with toluene (2x 25 ml.) and the combined organic phases were washed with water (2x 25 ml_), dried over Na2S04 and concentrated in vacuo (40°C/50-20 mbar), furnishing crude DMC as beige oil (5.7 g, 80.5% purity by quant. LC, 64% yield).
Example 6: Synthesis of 2.2-dimethylchroman-6-ol starting from 1 .4- hydroquinone and 2-methylbut-3-en-2-ol in the presence of Amberlyst 15 as acid catalyst A 200 ml. 4-necked sulfonation flask equipped with argon inlet, magnetic stirrer, oil bath and thermometer was charged with 8.0 g of 1 ,4-hydroquinone (72.2 mmol, 99.5%, 1 .9 mol equiv.) and 2-methyl-3-buten-2-ol (4.0 ml_, 39 mmol, 1 .0 mol equiv.), which were then suspended in 50 ml. of water and 43.5 g of toluene (50 ml_). Amberlyst 15 (4.0 g) was added and the two-phase reaction mixture was heated to reflux (83°C internal temperature) for 24 h. While still warm, the reaction mixture was then transferred to a separating funnel and the colorless phases were separated. The warm aqueous phase was extracted with toluene (2x 25 ml.) and the combined organic phases were washed with water (2x 25 ml_), dried over Na2S04 and concentrated in vacuo (40 °C/50-20 mbar), furnishing crude DMC as beige oil (5.8 g, 80.6% purity by quant. LC, 67% yield).
Examples 7-9:
The same reaction scale and conditions as in Example 5 were applied to other catalysts. The results are as follows:
“mol equiv.” = mol equivalent(s);“cone.” = concentration;“aq.” = aqueous;
“quant.” = quantitative;“LC” = liquid chromatography. Examples 10-13: Optimization of concentration and MBE dosage
In order to reduce HQ mol equivalents as well as the amount of toluene and sulfuric acid needed, MBE was added over a 2 hour-period, thus maximizing the ratio of HQ/MBE. As a result, the space-time yield could be improved by reducing the amount of solvents by a factor of 3 and the amount of HQ present in every cycle by a factor of 2. The yield decreased only slightly (from 83 to 79%).
Table 1. Compromise between excess HQ, sulfuric acid concentration and reaction volume.
overall concentration of MBE calculated for both phases
† combined chemical yield relative to MBE as analyzed in both liquid phases. The amount of product in the aqueous phase typically equals 1 -3 mol% yield.
Comparison example: Example 14: Synthesis of 2.2-dimethylchroman-6-ol (“DM- chromanol”) starting from 1 .4-hydroquinone (“HQ”) and 2-methylbut-3-en-2-ol (“MBE”) according to the conditions disclosed in US 4,217,285 , i.e. in the presence of ZnCb, silica-alumina and concentrated hydrochloric acid
95 C (reflux), 4 h
* iO ·, *. ' ! i MBE (1 0 eq). DM-chromanoi
39 mmof yield; 1.2%
purity; 5.9% eq.” = mol equivalents, h = hours.

Claims

Claims
1 . A process for the manufacture of a compound of formula (III),
comprising the step of reacting a compound of formula (I) with a compound of formula (IIA), (MB) or (IIC) in the presence of an acid catalyst and in a mixture of two solvents,
(I) (IIA) (MB) (IIC) wherein OR is OH, acetate, methanoate, propionate, butyrate or benzoate, A is CH2,
R1 is Ci-5-alkyl,
R2 is either H or Ci-2-alkyl,
R4 is either H or Ci-4-alkoxy or Ci-4-alkyl,
R3 and R5 are independently from each other either H or Ci-4-alkyl, and the first of the two solvents is water,
and the second of the two solvents is selected from aliphatic C5-8- hydrocarbons, cycloaliphatic Cs-s-hydrocarbons, dialkyl ethers and methyl- substituted benzenes and any mixture thereof.
2. The process according to claim 1 , wherein OR is OH or acetate, and/or R1 is methyl, and/or R4 is either H or methoxy or methyl, preferably R4 is either H or methoxy.
3. The process according to claim 1 and/or 2, wherein R3 and R5 are
independently from each other either H or methyl, and/or R2 is H or methyl, preferably R2 is methyl.
4. The process according to any one or more of the preceding claims, wherein the first of the two solvents is water and the second of the two solvents is selected from either hexane, cyclohexane, heptane, mesitylene, pseudocumene, methyl tert- butyl ether, ortho-xylene, meta-xylene, para-xylene or toluene, preferably wherein the first of the two solvents is water and the second of the two solvents is mesitylene, pseudocumene, ortho-xylene, meta-xylene, para- xylene or toluene, more preferably wherein the first of the two solvents is water and the second of the two solvents is ortho-xylene, meta-xylene, para- xylene or toluene, most preferably wherein the first of the two solvents is water and the second of the two solvents is toluene.
5. The process according to any one or more of the preceding claims, wherein the volume ratio of the first solvent to the second solvent during the reaction is in the range of 1 :4 to 4:1 , preferably wherein the volume ratio of the first solvent to the second solvent is in the range of 1 :3 to 3:1 most preferably wherein the volume ratio of the first solvent to the second solvent is in the range of 1 :2 to 2:1 .
6. The process according to any one or more of the preceding claims, wherein the total amount of the two solvents is in the range of 1 to 8 kg, preferably in the range of 2 to 6 kg, more preferably in the range of 2.5 to 5.5 kg, per kg of the compound of formula (I).
7. The process according to any one or more of the preceding claims, wherein the acid catalyst is selected from Bronsted acids, Lewis acids and any mixtures thereof, preferably wherein the acid catalyst is sulfuric acid, hydrochloric acid, formic acid, Amberlyst 15, trifluoroacetic acid, or phosphoric acid, more preferably wherein the acid catalyst is sulfuric acid, hydrochloric acid or Amberlyst 15, most preferably wherein the acid catalyst is sulfuric acid.
8. The process according to any one or more of the preceding claims, wherein the acid catalyst is sulfuric acid and the concentration of said sulfuric acid is in the range of from 0.1 to 10 mol/L, preferably wherein the concentration of said sulfuric acid is in the range of 0.4 to 4.0 mol/L.
9. The process according to any one or more of the preceding claims, wherein the amount of the acid catalyst is in the range of 0.01 to 10 mol equivalents, preferably in the range of 0.05 to 5 mol equivalents, more preferably in the range of 0.1 to 1 mol equivalents, relative to the amount of compound of formula (IIA), (MB), or (IIC).
10. The process according to any one or more of the preceding claims, wherein the molar ratio of the compound of formula (I) to the compound of formula (IIA), (MB) or (IIC) is in the range of 6.0:1 to 1.1 : 1 , preferably in the range of 4.0:1 to 1 .3:1 , even more preferably in the range of from 3.0:1 to 1 .5: 1 , most preferably in the range of 2.5:1 to 1 .7: 1 .
1 1 . The process according to any one or more of the preceding claims, wherein the reaction is carried out at a temperature in the range of 50 to 140°C, preferably in the range of 60 to 120°C, more preferably in the range of 70 to 100°C, most preferably in the range of 75 to 90° C.
12. The process according to any one or more of the preceding claims, wherein the reaction is carried out at a pressure in the range of 0.5 to 20 bar (absolute), preferably at a pressure in the range of 0.7 to 10 bar (absolute), most preferably at a pressure in the range of 0.8 to 5 bar (absolute).
13. The process according to any one or more of the preceding claims, wherein the acid catalyst is reusable.
EP19713808.4A 2018-03-29 2019-03-29 Process for the manufacture of chroman-6-ols with short side chains Withdrawn EP3774756A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18164861 2018-03-29
PCT/EP2019/058064 WO2019185900A1 (en) 2018-03-29 2019-03-29 Process for the manufacture of chroman-6-ols with short side chains

Publications (1)

Publication Number Publication Date
EP3774756A1 true EP3774756A1 (en) 2021-02-17

Family

ID=61837639

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19713808.4A Withdrawn EP3774756A1 (en) 2018-03-29 2019-03-29 Process for the manufacture of chroman-6-ols with short side chains

Country Status (3)

Country Link
EP (1) EP3774756A1 (en)
CN (1) CN111936483A (en)
WO (1) WO2019185900A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4040982A1 (en) 2019-10-11 2022-08-17 DSM IP Assets B.V. New feed additives of fat-soluble vitamins
WO2022078924A1 (en) 2020-10-12 2022-04-21 Dsm Ip Assets B.V. New feed additives of fat-soluble vitamins
WO2022112587A1 (en) 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New formulations with reduced antioxidant content, their manufacture and use
WO2022112585A1 (en) 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New sugar-free formulations, their manufacture and use
WO2022112592A1 (en) 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New formulations with reduced antioxidant content, their manufacture and use
WO2022112586A1 (en) 2020-11-30 2022-06-02 Dsm Ip Assets B.V. New sugar-free formulations, their manufacture and use
WO2022129433A1 (en) 2020-12-18 2022-06-23 Dsm Ip Assets B.V. Milk replacer comprising animal-free formulations of fat-soluble vitamins
CN116669565A (en) 2020-12-18 2023-08-29 帝斯曼知识产权资产管理有限公司 Animal-free milk substitutes containing fat-soluble vitamins

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE755758A (en) 1969-09-06 1971-02-15 Bayer Ag PROCESS FOR PREPARING CELLULAR POLYURETHANE MATERIALS IN THE PRESENCE OF COLOR STABILIZERS
US4217285A (en) * 1976-09-29 1980-08-12 Nisshin Flour Milling Co., Ltd. Process for the preparation of Dl-α-tocopherol of high purity
EP0782993B1 (en) * 1996-01-05 2003-02-26 F. Hoffmann-La Roche Ag Process for the preparation of d,l-alpha-tocopherol in the presence of a perfluoroalkenesulfonic acid catalyst
DE112004001149B4 (en) * 2003-07-08 2020-08-20 Dsm Ip Assets B.V. Production of tocopherols using a bismuth catalyst
DE602004017217D1 (en) * 2003-12-05 2008-11-27 Dsm Ip Assets Bv PROCESS FOR PREPARING ALKENYLATED HYDROXYLATED AROMATIC COMPOUNDS, CHROMAN COMPOUNDS AND THEIR ACYLATED DERIVATIVES

Also Published As

Publication number Publication date
CN111936483A (en) 2020-11-13
WO2019185900A1 (en) 2019-10-03

Similar Documents

Publication Publication Date Title
WO2019185900A1 (en) Process for the manufacture of chroman-6-ols with short side chains
FI60194C (en) FREQUENCY REFRIGERATION FOR BENSIL MONOKETALER
US7186850B2 (en) Synthesis of cannabinoids
US20100298579A1 (en) Process for preparing synthetic cannabinoids
EP2058320A1 (en) Process for preparing water-soluble phosphonooxymethyl derivatives of alcohol and phenol
US5107030A (en) Method of making 2,7-dimethyl-2,4,6-octatrienedial and derivatives thereof
US8697919B2 (en) 1-methoxyl-2, 6, 10-trimethyl-1, 3, 5, 9-undec-tetraene, and preparation method and uses thereof
JP6807396B2 (en) Method for preparing high-purity cyclohexenone long-chain alcohol
US6329535B1 (en) Process for preparing esterified chroman compounds
US5387718A (en) Method of manufacturing alkylphenyl alkyl ethers or alkylphenyl alkyl thioethers
KR20210119398A (en) Method for preparing 4-(2,2,3,3-tetrafluoropropyl)morpholine
RU2247707C2 (en) Method for production of 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanole
WO2015028463A1 (en) Formation of chromanes and chromenes by using silver(i) or gold(i) salts or complexes
KR102247402B1 (en) Method for producing cyclobutanetetracarboxylic acid and anhydride thereof
US4113969A (en) Preparation of 2,2-dimethyl-3-(2,2-dihalogenovinyl)-cyclopropane-1-carboxylic acid esters
US20110196170A1 (en) Method for producing astaxanthin dimethyldisuccinate
Morikawa et al. Sc (OTf) 3-catalyzed cyclooligomerization of 2, 4-dialkoxybenzyl alcohols. Formation of resorcin [n] arene peralkyl ethers
US5292947A (en) Process for preparing alkylsulfonic anhydrides
EP1871757B1 (en) Process for the manufacture of hydroxylated isoflavones
Hennis et al. 6H, 12H-6, 12-Methanodibenzo [b, f][1, 5] dioxocines from the reactions of o-alkenylphenols and salicylaldehydes
KR20020074263A (en) Process for preparing esterified chroman compounds
SU1179921A3 (en) Method of producing ehtyl esters of 1-methyl-or 1,4-dimethyl-1h-pyrrole-2-acetic acid
WO2025213198A1 (en) Chemistry process for the production of cannabinoid compounds
KR20230012705A (en) Process for Preparing Gossypetin
SU921462A3 (en) Method of producing 2-(3-benzoilphenyl)-propionic acid

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200925

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20221006

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20230217