CN111936483A - Process for preparing chroman-6-ols having short side chains - Google Patents
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- CN111936483A CN111936483A CN201980023720.0A CN201980023720A CN111936483A CN 111936483 A CN111936483 A CN 111936483A CN 201980023720 A CN201980023720 A CN 201980023720A CN 111936483 A CN111936483 A CN 111936483A
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- 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
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Abstract
The present invention relates to a process for the preparation 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) wherein OR is OH, acetate, formate, propionate, butyrate OR benzoate and A is CH, in the presence of an acid catalyst and in a mixture of two solvents2，R1Is C1‑5-alkyl, R2Is H or C1‑2-alkyl, R4Is H or C1‑4-alkoxy or C1‑4-alkyl, R3And R5Independently of one another, H or C1‑4-an alkyl group, and the first of the two solvents is water, and the second of the two solvents is selected from aliphatic C5‑8Hydrocarbon, alicyclic C5‑8Hydrocarbons, dialkyl ethers and methyl-substituted benzenes and their derivativesAnd (c) what mixture.
Description
Disclosure of Invention
The invention relates to a method for producing compounds 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, formate, propionate, butyrate OR benzoate,
a is CH2，
R1Is C1-5-an alkyl group,
R2is H or C1-2-an alkyl group,
R4is H or C1-4-alkoxy or C1-4-an alkyl group,
R3and R5Independently of one another, H or C1-4-an alkyl group, and
the first of the two solvents is water,
the second of the two solvents is selected from aliphatic C5-8Hydrocarbon, alicyclic C5-8Hydrocarbons, dialkyl ethers and methyl-substituted benzenes, and any mixtures thereof.
Background
Wang, x.she, x.ren, j.ma, x.pan describe the condensation of 2-methylbut-3-en-2-ol with 1, 4-hydroquinone ("HQ") to 2, 2-dimethylbenzopyran-6-ol ("DMC";a compound of the formula (III-1)) The yield was 56% ("The First asymmetry Total Synthesis of seal 3,4-Dihydroxy-2,2-Dimethyl-Chroman Derivatives (Several 3,4-Dihydroxy-2, 2-bis)First asymmetric total synthesis of methyl-chroman derivatives) ", Tetrahedron: Asymmetry, 2004, vol.15, No. 1, p.29-34).
Reactions using trifluoroacetic acid as the reaction medium (yield of DMC 33%) have also been described (see f.m.d. ismail, m.j.hilton,
"Versatile Synthesis of Benzopyrans via Ortho-Claisen Rearrangement of Allyl Ethers" (for multifunctional Synthesis of Benzopyrans via Allyl ether), Tetrahedron Lett.1992.
Alternatively, the reaction may be carried out using isoprene according to various publications, with yields between 53 and 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-Lipoygene by Marine-Derived Meroditers and Synthetic microorganisms" ("Redox Class of Marine-Derived diterpenes and Synthetic chromans for the Redox Inactivation of Human 15-Lipoxygenase: a Unique type of selectivity and Recyclable inhibitor prototype J.Am.Chem.2004, 126, 14910-20; G.P.149a.Valen.A.Valenc.A.:<<amberlyst 15 Catalyzed acylation of Phenols: One-Step Synthesis of benzopyran. "(Amberlyst 15 catalyzes allylation of phenol: One-Step Synthesis of benzopyran), Molecules 1997,2, 100-105 (using Amberlyst 15 in THF/heptane, 65-70 ℃,2.5h, 61%); ahluwallia, K.K.Arora, R.S.Jolly: "Acid-catalyzed condensation of isoprene with phenol. formation of 2, 2-dimethylchromenes." (Acid-catalyzed condensation of isoprene with phenol), J.chem.Soc., Perkin Trans.11982, 335-338 (H.Chem.C.)3PO4) (ii) a Bigi, S.Carloni, R.Maggi, C.Muchetti, M.Rastelli, G.Sartori: "Reaction between phenol and Isoprene catalyzed Reaction between chroman and o-Isoprenylphenol." (Zeolite catalyzed Reaction between phenol and Isoprene. chroman and o-isopentenylphenol)Highly selective Synthesis), Synthesis 1998, 301-304 (zeolite HSZ-360, autoclave, 120 ℃,5h, 50% yield); nast, M.Dahm, K.Ley (Bayer): Polyurethane Foams Stabilized with 6-Hydroxy Chromans, DE 1945212 (H)3PO4Yield 62% in xylene/petroleum ether).
In addition, prenyl acetate has been shown to react with in (OTf)3(salts of rare earth indium) catalyzed HQ reaction (see v.vece, j.ricci, s.pouulin-Martini, p.nava, y.carissan, s.humbel,
"in (III) -catalyzed Tandem C-C and C-O Bond Formation between Phenols and Allylic acids" (in (III) catalyzed Formation of C-C and C-O bonds in series between phenol and allyl acetate ", Eur. J. org. chem.2010, 6239-6248). However, methylene chloride (a halogenated solvent) has to be used here. In addition, 10 molar equivalents of the phenolic compound has to be used with respect to 1 molar equivalent of allyl acetate. Although giving a yield of 94%, it is costly to find a way to recover the excess HQ. Thus, the yield relative to HQ was < 10%. Another disadvantage is that acetate is a stoichiometric by-product, whereas in 2-methyl-3-buten-2-ol ("MBE") the by-product is water and in isoprene there is no by-product.
The two-step synthesis of compounds of formula (III-2) has been described in the literature, the reaction scheme being shown in FIG. 1.
Step 1): with MeSO3H is a solvent; 50 mol% of P2O591% yield (see F.Camps, J.Coll, A.Messeguer, MAporic. s, S.Ricart, WS Bowers, DM Soderlund: "An Improved processed product for the Preparation of 2, 2-Dimethyl-4-chromanones." (An Improved process for the Preparation of 2, 2-Dimethyl-4-chromanone)) Synthesis, 1980, pages 725-727.
Step 2)：LiAlH4，Et2O, yield 87% (see P.Anastasis, P.E.Brown: "Analogues of anti-juvenile hormones." (analogs against juvenile hormones), J.chem.Soc., Perkin Trans.11982, 2013-2018.).
The overall yield of these two steps was 79%.
However, the yields currently provided by the processes known from the literature are not high enough for sustainable industrial processes. Therefore, there is a need to provide a sustainable industrial process for the manufacture of compounds of formula (III) in high yield based on compounds of formula (I), wherein the use of halogenated solvents is avoided.
Detailed Description
This need is therefore met by the present invention, which relates to a process for the preparation 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, formate, propionate, butyrate OR benzoate,
a is CH2，
R1Is C1-5-an alkyl group,
R2is H or C1-2-an alkyl group,
R4is H or C1-4-alkoxy or C1-4-an alkyl group,
R3and R5Independently of one another, H or C1-4-an alkyl group, and
the first of the two solvents is water,
the second of the two solvents is selected from aliphatic C5-8Hydrocarbon, alicyclic C5-8Hydrocarbons, dialkyl ethers and methyl-substituted benzenes, and any mixtures thereof.
Thus, the use of halogenated solvents is avoided. Advantageously, the acid catalyst used and the excess of compound of formula (I) can be reused simply by separating the product phase from the phase containing the catalyst and the excess of compound of formula (I).
Raw materials and products
OR is preferably OH OR acetate.
R1Preferably methyl.
R2Preferably H or methyl; more preferably R2Is methyl.
R4Preferably H or methoxy or methyl, more preferably R4Is H or methoxy.
R3And R5Preferably independently of each other, H or methyl.
In the context of the present invention, "alkyl" and "alkoxy" include straight and branched chain alkyl groups, respectively, as well as straight and branched chain alkoxy groups.
Figures 2-5 show the most preferred compounds used as starting materials and the most preferred compounds obtained by the process of the invention as products.
FIG. 2 shows the synthesis of 2, 2-dimethylchromen-2-ol (compound of formula (III-1)) starting from 1, 4-hydroquinone (compound of formula (I-1)) and 2-methylbut-3-en-2-ol (compound of formula (IIA-1)).
FIG. 3 shows the synthesis of 2, 2-dimethylchromen-2-ol (compound of formula (III-1)) starting from 1, 4-hydroquinone (compound of formula (I-1)) and isoprene (compound of formula (IIB-1)).
FIG. 4 shows the synthesis of 2, 2-dimethylchromen-2-ol (compound of formula (III-1)) starting from 1, 4-hydroquinone (compound of formula (I-1)) and isopentenyl (prenyl) derivatives (compound of formula (IIC-1)).
FIG. 5 shows the synthesis of 2, 2-dimethylchromen-2-ol (compound of formula (III-1)) starting from 1, 4-hydroquinone (compound of formula (I-1)) and prenol (prenol) (compound of formula (IIC-2)).
In a preferred embodiment of the invention, the molar ratio of compound of formula (I) to compound of formula (IIA), (IIB) or (IIC) is in the range of 6.0: 1-1.1: 1, more preferably in the range of 4.0: 1 to 1.3: 1, even more preferably in the range of 3.0: 1 to 1.5: 1, most preferably in the range of 2.5: 1 to 1.7: 1, in the above range.
In another embodiment of the invention, all embodiments of the invention relating to the above mentioned raw materials and preferred options are realized.
Solvent mixture
Aliphatic C5-8Preferred examples of hydrocarbons are hexane and heptane. The term "hexane" encompasses n-hexane as well as any mixture of isomers of hexane. The same applies to heptane.
Alicyclic C5-8A preferred example of a hydrocarbon is cyclohexane.
The alkyl groups in the dialkyl ethers may be the same or different, preferably they are different. Preferably, the alkyl group is an aliphatic straight chain C1-5Alkyl or branched C3-6An alkyl group. 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, o-xylene, m-xylene, p-xylene, mesitylene, pseudocumene, methyl tert-butyl ether or toluene, and any mixture thereof. More preferably, the second solvent is hexane, cyclohexane, heptane, o-xylene, m-xylene, p-xylene, mesitylene, pseudocumene, methyl tert-butyl ether or toluene.
In a preferred embodiment of the invention, the first of the two solvents is water and the second of the two solvents is selected from mesitylene, pseudocumene, o-xylene, m-xylene, p-xylene or toluene, more preferably the first of the two solvents is water and the second of the two solvents is selected from o-xylene, m-xylene, p-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 the above range.
In another embodiment of the invention the total amount of both solvents is in the range of 1 to 8kg per kg of compound of formula (I), preferably in the range of 2 to 6kg per kg of compound of formula (I), more preferably in the range of 2.5 to 5.5kg per kg of compound of formula (I).
In another embodiment of the invention, all embodiments of the invention with respect to the solvent and the preferred options as described above are realized.
Water may be added to the reaction mixture as it is or as an aqueous solution of the acid catalyst, which is preferably as described below, that is, 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 include the water contained in the aqueous solution of the acid catalyst.
Acid catalyst
Examples of suitable acid catalysts are bronsted and lewis acids and any mixtures 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, p-toluenesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, bis (perfluoroalkyl-sulfonyl) methane (R' SO)2)(R”SO2)CH2(wherein R 'and R' each independently represent formula CnF2n+1Wherein n is an integer of 1 to 10), tris (perfluorosulfonyl) methane (R' SO)2)(R“SO2)(R″′SO2) CH (wherein R ', R ' and R ' independently of each other represent formula CnF2n+1Wherein n is an integer from 1 to 10, and wherein at least two of R ', R' and R 'are the same perfluoroalkyl group, or R' represents a pentafluoro-phenyl (-C)6F5) R 'and R' each represent the same formula C as abovenF2n+1Perfluoroalkyl), methanetrisulfonic acid, and bis (trifluoromethyl-sulfonyl) imide, and any mixtures thereof, wherein a single catalyst is preferably used.
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、InCl3、InBr3、In(OTf)3、In(NTf2)3、La(OTf)3、Ce(OTf)3、Sm(OTf)3、Gd(OTf)3、Bi(OTf)3In the absence or presence of 2, 2-bipyridine and any mixtures thereof, wherein the use of a single catalyst is preferred.
Preferably, the acid catalyst is sulfuric acid, hydrochloric acid, formic acid, Amberlyst 15, trifluoroacetic acid or phosphoric acid or an aqueous solution/suspension thereof, 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 invention, the acid catalyst is sulfuric acid and the concentration of said sulfuric acid is in the range of 0.1 to 10mol/L, preferably wherein the concentration of said sulfuric acid is in the range of 0.4 to 4.0 mol/L.
In another preferred embodiment of the invention, the amount of acid catalyst is in the range of 0.01 to 10 molar equivalents, more preferably in the range of 0.05 to 5 molar equivalents, most preferably in the range of 0.1 to 1 molar equivalent, relative to the amount of compound of formula (IIA), (IIB) or (IIC).
In another embodiment of the invention, all embodiments of the invention relating to the above catalysts and preferred options are realized.
Reaction conditions
The reaction is preferably carried out at a temperature in the range of from 50 to 140 ℃, more preferably at a temperature in the range of from 60 to 120 ℃, even more preferably at a temperature in the range of from 70 to 100 ℃, most preferably at a temperature in the range of from 75 to 90 ℃.
The reaction is preferably carried out at a pressure in the range of from 0.5 to 20bar (absolute), more preferably in the range of from 0.7 to 10bar (absolute), most preferably in the range of from 0.8 to 5bar (absolute).
In one process according to the invention, the acid catalyst is recyclable (═ reusable), which is another advantage of the invention.
In another embodiment of the present invention, all embodiments of the present invention regarding the above reaction conditions and preferred options are realized.
In the most preferred embodiments of the invention, all embodiments of the invention with respect to starting materials, solvents, catalysts and reaction conditions (including the preferred options as described above) are achieved.
The invention will now be further illustrated in the following non-limiting examples.
Examples
Comparative example:
example 1: synthesis of 2, 2-dimethylchromen-2-ol starting from 1, 4-hydroquinone and 2-methylbut-3-en-2-ol
A 500ml flask, equipped with a reflux condenser, magnetic stirrer and a supply of argon, was charged with 18.6 g of hydroquinone (167 mmol, 99%, 2.0mol equivalents) at room temperature and dissolved in 250 g of formic acid (5.4 mol, 65 mol equivalents) and 70 g of water.
7.2g of 2-methylbut-3-en-2-ol (83mmol, 99%, 1.0mol eq.) are added and heated to reflux for 4h, during which time the colorless solution slowly turns black. The reaction mixture was then cooled and poured into 1200g of ice water and neutralized to pH 7 by careful small batch addition of successively (exothermic, evolution of carbon dioxide) 240g of sodium carbonate (2.25mol, technical grade) and 112g of sodium bicarbonate (1.27mol, technical grade). The light brown cloudy solution was extracted with 250mL of ethyl acetate and then with 100mL of ethyl acetate. The combined organic phases were washed with 100mL of brine (10% aqueous NaCl), then dried over sodium sulfate, filtered and evaporated at 40 ℃ C./200-10 mbar. The heterogeneous crude (31.5g) was digested in 50mL heptane/ethyl acetate (90/10w/w) and filtered. The filter cake (mainly HQ) was washed with 50mL heptane/ethyl acetate (90/10 w/w). The filtrate was concentrated in vacuo (40 ℃ C./200-10 mbar) to give the crude product (14.4 g). Purifying the material by column chromatography; gradient heptane to heptane/EtOAc 80:20(w/w) was eluted. The pure fractions were combined and concentrated in vacuo (40 ℃ C./200-10 mbar). The residue is dissolved in 30mL of dichloromethane and subsequently evaporated again to dryness (40 ℃ C./200-0.1 mbar) to give 5.6g of DMC as off-white crystals (31.4mmol, 98.5% purity by qNMR, 37% yield).
According to an embodiment of the invention: examples 2 to 13
Example 2: synthesis of 2, 2-dimethylchromen-2-ol starting from 1, 4-hydroquinone and 2-methylbut-3-en-2-ol
A200 mL 4-necked sulfonation flask equipped with an argon inlet, magnetic stirrer, oil bath, and thermometer was charged with 35.1g of hydroquinone (319mmol, 99.5%, 2.0mol equivalents) suspended in 77.7g of sulfuric acid (0.4M, 0.17 mol equivalents) and 43.5g of toluene (50 mL). The biphasic reaction mixture was heated to reflux (internal temperature 85 ℃) after which all hydroquinone was dissolved in the aqueous phase. Then, 14.0g of 2-methyl-3-buten-2-ol ("MBE") (159mmol, 98.0%, 1.0mol equivalent) was added to the refluxed reaction mixture over 2 hours. After the addition was complete, the reaction was stirred at 85 ℃ (internal temperature) for an additional 3 hours. While still warm, the reaction mixture was then transferred to a separatory funnel and the colorless phase was 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 (2X 25 mL). The aqueous phase was then back-extracted with toluene (45 g total of toluene (2X 26 mL)). The toluene solution was then concentrated in a rotary evaporator to provide 29.60g of crude DMC (75.4% by qLC, 78.7% chemical yield relative to MBE) as an oil in beige (beige). The crude material was purified at 0.3 mbar and 125 ℃ (internal temperature) in a distillation apparatus equipped with a Vigreux column (20cm) to give a fraction: 22.40g of DMC (97.0% by quantitative LC, 121.9mmol, isolated yield 76.5%), mp.74.5-75 ℃.
Example 3: synthesis of 2, 2-dimethylbenzopyran-6-one starting from 1, 4-hydroquinone and 2-methylbut-3-en-2-ol
Alcohol: recycling of catalyst and 1, 4-hydroquinone phase
In a 1.5 liter 4-neck sulfonation flask equipped with an argon inlet, magnetic stirrer, oil bath, and thermometer, 651g of the aqueous phase from the previous run (performed on the same scale as this run; hydroquinone, about 3mol equivalents, -1.17 mol, and sulfuric acid, -0.4M, 0.78 mol, 0.5mol equivalents, and-3 mol% product), and additional fresh hydroquinone (43.0 g, 390mmol, 99.5%, 1.0mol equivalents); and 2-methyl-3-buten-2-ol (33.7g, 387mmol, 99.0%, 1.0mol equivalent) dissolved in toluene (500 mL). The biphasic reaction mixture was heated to reflux (internal temperature 85 ℃) for 4 h. While still warm, the reaction mixture was then transferred to a separatory funnel and the colorless phase was separated. The aqueous phase (about 650g) containing sulfuric acid and excess HQ was retained for the next reaction cycle. The organic phase was washed with water (2X 250 mL). The aqueous phase was then back-extracted with toluene (250 mL). The toluene solution was then concentrated on a rotary evaporator to give crude 2, 2-dimethylchromen-6-ol as a beige oil (93.88g, 64.8% purity by quantitative LC, 88% yield).
Example 4: synthesis of 2, 2-dimethylbenzopyran-2-ol starting from 1, 4-hydroquinone and prenol (see FIG. 5)
A350 mL 4-necked sulfonation flask equipped with an argon inlet, magnetic stirrer, oil bath, and thermometer was charged with 17.5 g of 1, 4-hydroquinone (159mmol, 99.5%, 4.0mol equivalent) and prenol (3.45g, 39.7mmol, 99%, 1.0mol equivalent)), which was then suspended in 50mL of sulfuric acid (0.4M, 0.5mol equivalent) and 43.5g of toluene (50 mL). Heating the two-phase reaction mixture to reflux (Internal temperature 84 ℃) for 4.5 h. While still warm, the reaction mixture was then transferred to a separatory funnel and the colorless phase was separated. The warm aqueous phase was extracted with toluene (2X 25mL) and the combined organic phases were washed with water (2X 25mL) and Na2SO4Dried and concentrated in vacuo (40 ℃/50-20mbar) to give crude DMC as a beige oil (7.0g, 76.3% purity by quantitative LC, 76% yield).
Example 5: synthesis of 2, 2-dimethylbenzopyran-6-ol starting from 1, 4-hydroquinone and isoprene (see FIG. 1)
3)
A200 mL 4-necked sulfonation flask equipped with an argon inlet, magnetic stirrer, oil bath, and thermometer was charged with 17.8g of 1, 4-hydroquinone (161mmol, 99.5%, 4.0mol equiv.) and isoprene (2.75g, 40.4mmol, 1.0mol equiv.), which was then suspended in 50mL of sulfuric acid (0.4M, 0.5mol equiv.) and 43.5g of toluene (50 mL). The biphasic reaction mixture was heated to reflux (internal temperature slowly raised to 82 ℃ during reflux; oil bath at 100 ℃) for 26 hours. While still warm, the reaction mixture was then transferred to a separatory funnel and the colorless phase was separated. The warm aqueous phase was extracted with toluene (2X 25mL) and the combined organic phases were washed with water (2X 25mL) and Na2SO4Dried and concentrated in vacuo (40 ℃/50-20mbar) to give crude DMC as a beige oil (5.7g, 80.5% purity by quantitative LC, 64% yield).
Example 6: in the presence of Amberlyst 15 as acid catalyst, from 1, 4-hydroquinone and 2-methylbut-3-ene-
2-alcohol Synthesis of 2, 2-Dimethylchroman-6-ol
A200 mL 4-neck sulfonation flask equipped with an argon inlet, magnetic stirrer, oil bath, and thermometer was charged with 8.0 grams of 1, 4-hydroquinone (72.2mmol, 99.5%, 1.9 molar equivalents) and 2-methyl-3-buten-2-ol (4.0mL, 39mmol, 1.0 molar equivalents), which was then suspended in 50mL of water and 43.5g of toluene (50 mL). Amberlyst 15(4.0g) was added and the biphasic reaction mixture was heated to reflux (internal temperature 83 ℃) for 24 hours. While still warm, the reaction mixture was then transferred to a separatory funnel and separatedAnd (3) color phase. The warm aqueous phase was extracted with toluene (2X 25mL) and the combined organic phases were washed with water (2X 25mL) and Na2SO4Dried and concentrated in vacuo (40 ℃/50-20mbar) to give crude DMC as a beige oil (5.8g, 80.6% purity by quantitative LC, 67% yield).
Examples 7 to 9:
the same reaction scale and conditions as in example 5 were applied to the other catalysts. The results are as follows:
"mol equiv." -molar equivalents; concentration, "—"; "aq." is water; quantitative; "LC" ═ liquid chromatography.
Examples 10 to 13: optimization of concentration and MBE dose
To reduce the HQ molar equivalents and the required amount of toluene and sulfuric acid, MBE was added over a 2 hour period, thereby maximizing the HQ/MBE ratio. As a result, the space-time yield can be increased by reducing the amount of solvent to 1/3 and the amount of HQ present in each cycle to 1/2. The yield decreased only slightly (from 83% to 79%).
TABLE 1 compromise between excess HQ, sulfuric acid concentration and reaction volume
Total concentration of MBE calculated for two stages
The amount of product in the aqueous phase is generally equivalent to a yield of 1-3 mol%.
Comparative example: example 14: from 1, 4-Hydroquinone ("HQ") and 2-methylbut-3-en-2-ol ("MBE") according to the United states patent
2The conditions disclosed in Li 4,217,285, i.e. starting the synthesis of 2,2-
Dimethylbenzopyran-2-ols ("DM-benzopyranols")
"eq." -molar equivalent, h-hour.
Claims (13)
1. A process for the preparation 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, formate, propionate, butyrate OR benzoate,
a is CH2，
R1Is C1-5-an alkyl group,
R2is H or C1-2-an alkyl group,
R4is H or C1-4-alkoxy or C1-4-an alkyl group,
R3and R5Independently of one another, H or C1-4-an alkyl group, and
the first of the two solvents is water,
the second of the two solvents is selected from aliphatic C5-8Hydrocarbon, alicyclic C5-8Hydrocarbons, dialkyl ethers and methyl-substituted benzenes, and any mixtures thereof.
2. A process according to claim 1, wherein OR is OH OR acetate, and/OR R1Is methyl, and/or R4Is H or methoxy or methyl, preferably, R4Is H or methoxy.
3. Process according to claim 1 and/or 2, wherein R3And R5Independently of one another, H or methyl, and/or R2Is H or methyl, preferably, R2Is 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 cyclohexane, hexane, heptane, mesitylene, pseudocumene, methyl tert-butyl ether, o-xylene, m-xylene, p-xylene or toluene, preferably wherein the first of the two solvents is water and the second of the two solvents is mesitylene, pseudocumene, o-xylene, m-xylene, p-xylene or toluene, more preferably wherein the first of the two solvents is water and the second of the two solvents is o-xylene, m-xylene, p-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, in the above range.
6. The method 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 8kg per kg of compound of formula (I), preferably in the range of 2 to 6kg per kg of compound of formula (I), more preferably in the range of 2.5 to 5.5kg per kg of compound of formula (I).
7. The process according to any one or more of the preceding claims, wherein the acid catalyst is selected from the group consisting of bronsted acids, lewis acids and any mixture 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 the sulfuric acid is in the range of 0.1 to 10mol/L, preferably wherein the concentration of the 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 molar equivalents, preferably in the range of 0.05 to 5 molar equivalents, more preferably in the range of 0.1 to 1 molar equivalents, relative to the amount of the compound of formula (IIA), (IIB) 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), (IIB) 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 3.0: 1 to 1.5: 1, most preferably in the range of 2.5: 1 to 1.7: 1, in the above range.
11. 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 from 50 to 140 ℃, preferably at a temperature in the range of from 60 to 120 ℃, more preferably at a temperature in the range of from 70 ℃ to 100 ℃, most preferably at a temperature in the range of from 75 to 90 ℃.
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 from 0.5 to 20bar (absolute), preferably in the range of from 0.7 to 10bar (absolute), most preferably in the range of from 0.8 to 5bar (absolute).
13. A process according to any one or more of the preceding claims, wherein the acid catalyst is reusable.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP18164861 | 2018-03-29 | ||
| EP18164861.9 | 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 |
|---|---|
| CN111936483A true CN111936483A (en) | 2020-11-13 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980023720.0A Withdrawn CN111936483A (en) | 2018-03-29 | 2019-03-29 | Process for preparing chroman-6-ols having short side chains |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP3774756A1 (en) |
| CN (1) | CN111936483A (en) |
| WO (1) | WO2019185900A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022078924A1 (en) | 2020-10-12 | 2022-04-21 | Dsm Ip Assets B.V. | New feed additives of fat-soluble vitamins |
| CN116490080A (en) | 2020-11-30 | 2023-07-25 | 帝斯曼知识产权资产管理有限公司 | New formulation with reduced antioxidant content, its 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 |
| WO2022112585A1 (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 formula comprising fat-soluble vitamins |
Family Cites Families (5)
| 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 |
| DE59610172D1 (en) * | 1996-01-05 | 2003-04-03 | Hoffmann La Roche | Process for the preparation of d, l-alpha-tocopherol in the presence of a perfluoroalkylene sulfonic acid as a catalyst |
| WO2005005407A1 (en) * | 2003-07-08 | 2005-01-20 | Dsm Ip Assets B.V. | Manufacture of tocopherols using a bismuth catalyst |
| ATE411307T1 (en) * | 2003-12-05 | 2008-10-15 | Dsm Ip Assets Bv | METHOD FOR PRODUCING ALKENYLATED HYDROXYLATED AROMATIC COMPOUNDS, CHROME COMPOUNDS AND THEIR ACYLATED DERIVATIVES |
-
2019
- 2019-03-29 CN CN201980023720.0A patent/CN111936483A/en not_active Withdrawn
- 2019-03-29 WO PCT/EP2019/058064 patent/WO2019185900A1/en active Application Filing
- 2019-03-29 EP EP19713808.4A patent/EP3774756A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP3774756A1 (en) | 2021-02-17 |
| WO2019185900A1 (en) | 2019-10-03 |
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