WO1997028151A1 - PROCEDE DE PREPARATION DE DL-α-TOCOPHEROL OU DE DL-α-TOCOPHERYLACETATE - Google Patents

PROCEDE DE PREPARATION DE DL-α-TOCOPHEROL OU DE DL-α-TOCOPHERYLACETATE Download PDF

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Publication number
WO1997028151A1
WO1997028151A1 PCT/EP1997/000324 EP9700324W WO9728151A1 WO 1997028151 A1 WO1997028151 A1 WO 1997028151A1 EP 9700324 W EP9700324 W EP 9700324W WO 9728151 A1 WO9728151 A1 WO 9728151A1
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WO
WIPO (PCT)
Prior art keywords
reaction
acid
tocopherol
solvent
carbonate
Prior art date
Application number
PCT/EP1997/000324
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German (de)
English (en)
Inventor
Hagen Jaedicke
Paul Grafen
Harald Laas
Original Assignee
Basf Aktiengesellschaft
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
Priority claimed from DE1996103142 external-priority patent/DE19603142A1/de
Priority claimed from DE1996117444 external-priority patent/DE19617444A1/de
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to EP97901601A priority Critical patent/EP0882036A1/fr
Priority to JP52727997A priority patent/JP2002502360A/ja
Publication of WO1997028151A1 publication Critical patent/WO1997028151A1/fr

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    • 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 invention relates to an improved process for the preparation of dl- ⁇ -tocopherol (vitamin E) or dl- ⁇ -tocopheryl acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with a phytol and, if appropriate, subsequent esterification with Acet anhydride.
  • vitamin E dl- ⁇ -tocopherol
  • TSH 2,3,5-trimethylhydroquinone
  • vitamin E It is already known to produce vitamin E by reacting TMH and a phytol, for example isophytol (IP) at elevated temperature in a slightly polar solvent in the presence of various acidic catalysts.
  • IP isophytol
  • reaction can be carried out in the presence of SiO 2 / Al 2 O 3 with acids.
  • the reaction can also be carried out in the presence of ZnCl 2 in combination with acids, such as hydrohalic acids, in particular HCl, trichloroacetic acid or acetic acid.
  • acids such as hydrohalic acids, in particular HCl, trichloroacetic acid or acetic acid.
  • ZnCl 2 can also be used in a mixture with NaHS0 4 , sulfuric acid or p-toluenesulfonic acid in a molar ratio of 1: 3 to 1: 1.
  • the reaction in the presence of a mixture of Si0 2 and A1 2 0 3 in a ratio of 87:13 can be carried out as a catalyst in perchlorethylene.
  • vitamin E is obtained by reacting phytol or isophytol with TMH in an inert solvent using a macroreticular cation exchange resin of the sulfonic acid type.
  • reaction according to DE 27 43 920 in the presence of a mixture of silica / aluminum oxide or silica gel and zinc chloride and a strong acid, such as concentrated HCl, H 2 S0 4 , H 3 P0 4 or p-toluenesulfonic acid.
  • a strong acid such as concentrated HCl, H 2 S0 4 , H 3 P0 4 or p-toluenesulfonic acid.
  • a disadvantage of this process is that corrosion problems occur and that the waste water can be contaminated with zinc ions.
  • the reaction is carried out in the presence of a mixture of ortho-boric acid on the one hand and oxalic acid, tartaric acid or citric acid on the other hand.
  • alkyl aromatic compounds such as toluene and xylene or ketones such as diethyl ketone or methyl isopropyl ketone are proposed as solvents for the reaction.
  • a disadvantage of this process is that non-polar aprotic solvents, such as benzine, heptane, toluene and xylene, have only a small amount of bulk for inorganic acids and TMH.
  • benzine, heptane, toluene and xylene have only a small amount of bulk for inorganic acids and TMH.
  • methanol must therefore be added to the reaction mixture, which takes up excess TMH and the catalyst acid in a polar lower phase before vitamin E can be isolated.
  • 5-ring carbonates such as 1,2-propylene carbonate
  • the open-chain carbonates and 5-ring carbonates also differ in their other loose properties considerably.
  • the dialkyl carbonates are readily miscible with hydrocarbons, such as hexane, while the 5-ring carbonates are practically immiscible with hydrocarbons, such as hexane.
  • the invention accordingly relates to a process for the preparation of dl- ⁇ -tocopherol or dl- ⁇ -tocopheryl acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol or isophytol (IP) in a solvent at elevated Temperature and optionally subsequent esterification of the tocopherol obtained with acetic anhydride, which is characterized in that the reaction of TMH with phytol or IP in a cyclic carbonate of the general formula I or a ⁇ -lactone of the general formula II
  • R x , R 2 and R 3 are H; Methyl or ethyl, preferably H or methyl
  • R 4 is H, phenyl or optionally by phenyl or
  • Oxygen-containing groups substituted alkyl with a total of up to 20 carbon atoms preferably represents H, methyl, ethyl, isopropyl, phenyl or methoxymethyl,
  • R 1 , R 2 and R 3 are H; Methyl or ethyl, preferably ⁇ example are H or methyl
  • R 4 represents H, phenyl or alkyl which may be substituted by phenyl or oxygen-containing groups and has a total of up to 20 carbon atoms, preferably H, methyl, ethyl, isopropyl, phenyl or methoxymethyl,
  • the tocopherol which separates as the upper phase when the reaction mixture is cooled and / or the reaction mixture is extracted with a suitable aliphatic hydrocarbon and the tocopherol is isolated from the extract by distillation and the cyclic carbonate or cyclic carbonate which may have been removed and may contain excess TMH and acid catalyst ⁇ -lactone used again as a solvent.
  • reaction is carried out as an azeotrope with a suitable hydrocarbon by separating off the water formed in the reaction and / or if the reaction is carried out in the presence of a mixture of ortho-boric acid on the one hand and oxalic acid, tartaric acid or Citric acid on the other hand, or in the presence of BF 3 etherate as an acid catalyst.
  • Particularly suitable cyclic 5-ring carbonates are ethylene carbonate, propylene carbonate, 1,2-butylene carbonate or isobutylene carbonate, preferably propylene carbonate.
  • Particularly suitable 5-ring lactones of the formula II are ⁇ -butyrolactone, 3-methyl- ⁇ -butyrolactone, 3,4-dimethyl- ⁇ -butyro-lactone, 4,5-dimethyl- ⁇ -butyrolactone and 5-ethyl ⁇ -butyrolactone, especially called ⁇ -butyrolactone.
  • TMH and phytol or isophytol are known and therefore need not be discussed.
  • TMH and IP can be used in a molar ratio of about 1: 1, but it is also possible to use one of the reactants in excess. Particularly good yields are obtained if TMH and IP are converted in a molar ratio of about 1.5 to 1. Here, unreacted TMH remains in the solvent and can be reacted with it again.
  • Suitable acidic catalysts are in principle all catalysts known from the prior art for the reaction of TMH with phytol or IP, provided they do not cause the cyclic carbonates or ⁇ -lactones used as solvents to decompose, such as, for example, with ZnCl 2 in the cyclic carbonates is the case.
  • catalysts which do not cause any corrosion problems and / or do not have a strong contamination of the waste water with metal ions or inorganic acids and which are sufficiently strong to carry out the reaction sufficiently quickly.
  • the process is particularly advantageous if a mixture of ortho-boric acid on the one hand with oxalic acid, tartaric acid or citric acid on the other hand is used as the acid catalyst.
  • the ortho-boric acid presumably forms complexes with the dicarboxylic acids mentioned, which have the advantageous effect.
  • the ortho-boric acid and the dicarboxylic acids mentioned are advantageously used in a molar ratio of about 1: 1 to 1: 5, preferably about 1: 2.
  • This mixture is used in amounts of about 0.1% to 10% by weight, preferably 0.5 to 4% by weight, based on the TMH used.
  • BF 3 etherate is used, the reaction is successful with amounts of 0.5 to 3, preferably 1 to 1.5,% by weight of BF 3 ⁇ C 2 Hs • OC 2 H 5 , based on TMH.
  • BF 3 etherate When 10% by weight of BF 3 etherate is used, strong phytadiene formation lowers the yield which can be achieved; If only 0.1% by weight is used, vitamin E is no longer formed.
  • acidic ion exchangers which are stable under the reaction conditions, such as Amberlyte ® 15, can also be used as catalysts.
  • R 1 to R 4 are H or methyl
  • the cyclic 5-ring carbonates are or R 1 to R 3 is H or methyl and R 4 is ethyl
  • R 1 to R 3 can additionally represent ethyl
  • R 4 additionally represents phenyl or one optionally by phenyl or oxygen -containing groups, such as the phenoxy group, one or more alkoxy groups, a carboxyl group or an alkoxycarbonyl group, substituted alkyl group with a total of at most 20 carbon atoms.
  • R 4 is preferably H, methyl, ethyl, isopropyl, phenyl or methoxymethyl.
  • the cyclic carbonates used according to the invention can also be produced on an industrial scale at very low cost by reacting the corresponding alkylene oxides with CO 2 and the ⁇ -lactones of the formula II by catalytic dehydrogenation of the corresponding butanediols. They generally have such high boiling points that temperatures of 170 ° C can be easily reached under normal pressure. They are non-toxic (the LD 50 for rats, for example, is 1,2000 propylene carbonate orally at 29,000 mg / kg and for ethylene carbonate at 10,000 mg / kg), which is very important for the production of vitamins, and is good biodegradable (cf. company publication "Alkylencarbonate" from Hüls AG, July 1991).
  • TMH and IP are sufficiently accelerated in them for a continuous process. Side reactions such as phytadiene formation are suppressed in them.
  • the cyclic carbonates of the formula I in contrast to dialkyl carbonates, such as dimethyl carbonate, diethyl carbonate and methyl ethyl carbonate, - and the ⁇ -lactones of the formula II do not mix with pure aliphatic hydrocarbons, such as heptane, hexane or gasolines If necessary, the vitamin E can be completely extracted from the reaction mixture with these aliphatic hydrocarbons.
  • the water formed in the reaction surprisingly attacks the cyclic carbonates and ⁇ -latons in the presence of suitable acidic catalysts under the reaction conditions so little that, for example, when propylene carbonate is used as solvent and a mixture of ortho-boric acid and Oxalic acid as an acid catalyst after the reaction is detectable only less than 0.1% of a propylene glycol formed by hydrolysis.
  • the solvents can therefore be used again for up to 10 reaction cycles without any purification (cf. Examples 2 and 10).
  • the cyclic carbonate or ⁇ -laton separated after the isolation of vitamin E is fed into new reaction cycles with new TMH without addition of the acid catalyst. Residues of unreacted TMH remain in the solvent and are not lost.
  • the alkylene carbonates and the ⁇ -lactones are generally used in amounts of 0.2 to 2 liters, preferably 0.5 to 1 liter per mole of TMH.
  • reaction temperatures are generally 100 to 200 ° C., preferably 120 to 160 ° C., in particular 145 to 155 ° C., depending on the carbonate used, on the acid strength and amount of acid
  • reaction temperatures are generally 50 to 200 ° C., preferably 80 to 180 ° C., in particular 120 to 155 ° C., depending on the ⁇ -lactone used, depending on the acid strength and amount of acid
  • the procedure is advantageously carried out by heating TMH and the acid catalyst in the cyclic carbonate or the ⁇ -lactone to about 140 to 160 ° C. and at this temperature
  • tocopherol obtained in this way can either be isolated as such or else acid-catalyzed with excess acetic anhydride and converted into tocopheryl acetate and then - if desired - purified by fractional distillation under greatly reduced pressure.
  • the process can be carried out batchwise or continuously.
  • the reaction is generally carried out continuously in a reaction column into which, for example, a mixture of the cyclic carbonate or the ⁇ -lactone, the catalyst, TMH and IP and, if appropriate, a hydrocarbon is fed in laterally, the hydrocarbon and the like formed water at the top of the column and removes hot cyclic carbonate and vitamin E from the bottom.
  • a reaction column into which, for example, a mixture of the cyclic carbonate or the ⁇ -lactone, the catalyst, TMH and IP and, if appropriate, a hydrocarbon is fed in laterally, the hydrocarbon and the like formed water at the top of the column and removes hot cyclic carbonate and vitamin E from the bottom.
  • the tocopherol which precipitates on cooling is separated off and / or extracted with an aliphatic hydrocarbon.
  • dl- ⁇ -tocopherol or its acetate can be produced in a very simple and environmentally friendly manner in a very good yield and purity in a continuous manner.
  • example 1
  • TSH trimethylhydroquinone
  • the slightly colored solution was cooled and extracted with heptane. 41 g of pure tocopherol were isolated by distilling off heptane. This corresponds to a yield of 95% of theory, based on the isophytol used. In this extraction, 162 g of propylene carbonate were removed as the lower phase. It still contained the acid catalyst and residual amounts of heptane and can thus be used again as a solvent.
  • the unreacted TMH remained dissolved in the propylene carbonate and, after being supplemented with 15.2 g of fresh TMH and 0.1 g of fresh acid mixture (20% of the original amount), it could be reacted again in the manner described above. In this way, the propylene carbonate was used as a solvent nine times without intermediate cleaning. The remaining TMH, which was still present at the end, was reacted with 10.5 g of IP to dl- ⁇ -tocopherol without further additions and extracted with 100 ml of heptane.
  • reaction can also very advantageously be carried out continuously, with 10% of the lower phase being continuously passed into a cleaning stage.
  • the yield was therefore 94%, based on the IP used.
  • TMH 22.5 g was heated, together with 0.3 g of de products described in Example 2 acid mixture in 80 ml of ethylene carbonate at 140 C C.
  • a solution of 30 g of IP in 100 ml of heptane was added over the course of 20 min, while distilling off a water-heptane azeotrope. adds.
  • the mixture was then stirred for a further 30 min at 140 ° C., then cooled and extracted with 50 ml of heptane.
  • 46 g of residue containing 40 g of tocopherol were obtained in addition to solvent residues, corresponding to a yield of 93% of theory, based on the IP used.
  • TSH trimethylhydroquinone
  • IP isophytol
  • the slightly colored solution was cooled to 30 ° C. and extracted twice with 100 ml of heptane each time. 41.6 g of pure tocopherol were isolated by distilling off heptane. This corresponds to a yield of 96% of theory, based on the isophytol used.
  • the lower phase separated in this extraction contained, in addition to ⁇ -butyrolactone, the acid catalyst and residual amounts of heptane and was thus used again as a solvent.
  • the unreacted TMH was dissolved in ⁇ -butyrolactone and was complete after 15.2 g of fresh TMH and 0.1 g of fresh acid mixture (20% of the original amount) again in the above prescribed manner ⁇ be implemented.
  • reaction can also very advantageously be carried out continuously, with 10% of the lower phase being continuously passed into a cleaning stage.
  • the yield was therefore 96%, based on the IP used.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation de dl-α-tocophérol ou de dl-α-tocophérylacétate par réaction catalysée sous acide de 2,3,5-triméthyle-hydroquinone (TMH) avec du phytol ou de l'isophytol (IP) dans un solvant à température élevée et éventuellement ensuite par estérification du tocophérol obtenu avec de l'anhydride acétique. Ce procédé se caractérise en ce que la réaction est effectuée dans un carbonate cyclique à 5 chaînons éventuellement substitué, tel que du 1,2-propylène-carbonate ou un lactone substitué à 5 chaînons, tel que du η-butyrolactone, en tant que solvant, à des températures comprises entre 50 et 200 °C. La réaction est particulièrement avantageuse si, après la réaction du TMH avec du phytol ou de l'IP, on sépare le tocophérol qui se dépose comme phase supérieure pendant le refroidissement du mélange réactionnel et/ou si on extrait le mélange réactionnel avec un hydrocarbure aliphatique approprié, puis si le tocophérol est isolé de l'extrait par distillation et si le carbonate cyclique ou l'η-lactone contenant un surplus de TMH et de catalyseur acide est réutilisé comme solvant. Dans de nombreuses circonstances, il s'est avéré avantageux d'effectuer la réaction de TMH avec du phytol ou de l'IP par séparation de l'eau produite au titre d'azéotrope lors de la réaction, avec un hydrocarbure approprié et/ou en présence d'un mélange d'acide orthoborique d'une part et d'acide oxalique, d'acide tartrique ou d'acide citrique d'autre part, ou en présence de BF3-éthérat comme catalyseur. Etonnamment, les carbonates à 5 chaînons et les lactones à 5 chaînons se sont avérés très stables dans les conditions de réaction et ont montré un bon pouvoir solubilisateur, permettant d'effectuer un processus continu.
PCT/EP1997/000324 1996-01-29 1997-01-24 PROCEDE DE PREPARATION DE DL-α-TOCOPHEROL OU DE DL-α-TOCOPHERYLACETATE WO1997028151A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP97901601A EP0882036A1 (fr) 1996-01-29 1997-01-24 Procede de preparation de dl-alpha-tocopherol ou de dl-alpha-tocopherylacetate
JP52727997A JP2002502360A (ja) 1996-01-29 1997-01-24 ｄｌα―トコフェロールまたは酢酸ｄｌ―α―トコフェリルの製造方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE1996103142 DE19603142A1 (de) 1996-01-29 1996-01-29 Verfahren zur Herstellung von dl-alpha-Tocopherol oder dl-alpha-Tocopherylacetat
DE19603142.7 1996-01-29
DE19617444.9 1996-05-02
DE1996117444 DE19617444A1 (de) 1996-05-02 1996-05-02 Verfahren zur Herstellung von dl-alpha-Tocopherol oder dl-alpha-Tocopherylacetat

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WO1997028151A1 true WO1997028151A1 (fr) 1997-08-07

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EP (1) EP0882036A1 (fr)
JP (1) JP2002502360A (fr)
CN (1) CN1211243A (fr)
RU (1) RU2160258C2 (fr)
WO (1) WO1997028151A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0857722A1 (fr) * 1997-02-07 1998-08-12 Basf Aktiengesellschaft Procédé de préparation d'esters d'acide tocopherylcarboxyliques ou de tocotrienylesters par réaction catalysée acide avec des acides carboxiliques
EP0949255A1 (fr) * 1998-04-06 1999-10-13 F. Hoffmann-La Roche Ag Procédé pour la préparation de d,1-alpha-tocophérol en milieu solvant carbonate et avec un catalyseur acidique contenant le soufre
EP0970953A1 (fr) * 1998-07-10 2000-01-12 F. Hoffmann-La Roche AG La préparation de l'alpha-tocophérol
EP1172363A1 (fr) * 2000-07-10 2002-01-16 F. Hoffmann-La Roche Ag Procédé d'acylation
WO2002042286A1 (fr) * 2000-11-22 2002-05-30 Basf Aktiengesellschaft Procede d'acylation continue de derives d'esters de chromanol
US6444098B2 (en) 2000-07-10 2002-09-03 Roche Vitamins Inc. Process for the preparation of tocol acylates and tocopherol acylates
US6452023B1 (en) 1998-07-10 2002-09-17 Roche Vitamins Inc. Process for preparing d,l-α-tocopherol
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
WO2020035604A1 (fr) 2018-08-17 2020-02-20 Basf Se Synthèse de dérivés de chromanol
WO2020035600A1 (fr) 2018-08-17 2020-02-20 Basf Se Synthèse de dérivés de chromanol
WO2020035601A1 (fr) 2018-08-17 2020-02-20 Basf Se Synthèse de dérivés de chromanol et de 2-méthyl-1,4-naphtoquinone

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7435836B2 (en) * 2004-04-26 2008-10-14 Dsm Ip Assets B.V. Process for the manufacture of tocopheryl acylates
EP1954686B1 (fr) * 2004-08-19 2012-06-20 DSM IP Assets B.V. Procede de traitement d'un melange contenant de vitamine e et d'acetate de vitamine e
CN102336732A (zh) * 2011-07-14 2012-02-01 福建省福抗药业股份有限公司 一锅法制备维生素e乙酸酯的生产方法
CN104592191A (zh) * 2014-12-25 2015-05-06 浙江新和成药业有限公司 一种合成生育酚琥珀酸酯的方法

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JPS5315381A (en) * 1976-07-26 1978-02-13 Eisai Co Ltd Cynthesis of alpha-tocopherol
US4639533A (en) * 1982-07-29 1987-01-27 Basf Corporation Alpha tocopherol process
EP0694541A1 (fr) * 1994-07-27 1996-01-31 Eisai Co., Ltd. Procédé de préparation de alpha-tocophérol

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
JPS5315381A (en) * 1976-07-26 1978-02-13 Eisai Co Ltd Cynthesis of alpha-tocopherol
US4639533A (en) * 1982-07-29 1987-01-27 Basf Corporation Alpha tocopherol process
EP0694541A1 (fr) * 1994-07-27 1996-01-31 Eisai Co., Ltd. Procédé de préparation de alpha-tocophérol

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DATABASE WPI Week 7813, Derwent World Patents Index; AN 78-24010A, XP002029524 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6667048B1 (en) 1997-01-07 2003-12-23 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6982282B2 (en) 1997-01-07 2006-01-03 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6660286B1 (en) 1997-01-07 2003-12-09 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
EP0857722A1 (fr) * 1997-02-07 1998-08-12 Basf Aktiengesellschaft Procédé de préparation d'esters d'acide tocopherylcarboxyliques ou de tocotrienylesters par réaction catalysée acide avec des acides carboxiliques
US6365758B1 (en) 1997-02-07 2002-04-02 Basf Aktiengesellschaft Preparation of tocopheral carboxylates or tocotrienyl esters by acid-catalyzed reaction with carboxylic acids
EP0949255A1 (fr) * 1998-04-06 1999-10-13 F. Hoffmann-La Roche Ag Procédé pour la préparation de d,1-alpha-tocophérol en milieu solvant carbonate et avec un catalyseur acidique contenant le soufre
US6066745A (en) * 1998-04-06 2000-05-23 Roche Vitamins Inc. Process for the synthesis of vitamin E
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
EP0970953A1 (fr) * 1998-07-10 2000-01-12 F. Hoffmann-La Roche AG La préparation de l'alpha-tocophérol
US6452023B1 (en) 1998-07-10 2002-09-17 Roche Vitamins Inc. Process for preparing d,l-α-tocopherol
EP1172363A1 (fr) * 2000-07-10 2002-01-16 F. Hoffmann-La Roche Ag Procédé d'acylation
US6444098B2 (en) 2000-07-10 2002-09-03 Roche Vitamins Inc. Process for the preparation of tocol acylates and tocopherol acylates
US6784303B2 (en) 2000-11-22 2004-08-31 Basf Aktiengesellschaft Method for continuously acylating chromanol ester derivatives
WO2002042286A1 (fr) * 2000-11-22 2002-05-30 Basf Aktiengesellschaft Procede d'acylation continue de derives d'esters de chromanol
WO2020035604A1 (fr) 2018-08-17 2020-02-20 Basf Se Synthèse de dérivés de chromanol
WO2020035600A1 (fr) 2018-08-17 2020-02-20 Basf Se Synthèse de dérivés de chromanol
WO2020035601A1 (fr) 2018-08-17 2020-02-20 Basf Se Synthèse de dérivés de chromanol et de 2-méthyl-1,4-naphtoquinone
US11673874B2 (en) 2018-08-17 2023-06-13 Basf Se Synthesis of chromanol derivatives

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JP2002502360A (ja) 2002-01-22
RU2160258C2 (ru) 2000-12-10
EP0882036A1 (fr) 1998-12-09
CN1211243A (zh) 1999-03-17

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