EP0882036A1 - Procede de preparation de dl-alpha-tocopherol ou de dl-alpha-tocopherylacetate - Google Patents

Procede de preparation de dl-alpha-tocopherol ou de dl-alpha-tocopherylacetate

Info

Publication number
EP0882036A1
EP0882036A1 EP97901601A EP97901601A EP0882036A1 EP 0882036 A1 EP0882036 A1 EP 0882036A1 EP 97901601 A EP97901601 A EP 97901601A EP 97901601 A EP97901601 A EP 97901601A EP 0882036 A1 EP0882036 A1 EP 0882036A1
Authority
EP
European Patent Office
Prior art keywords
reaction
acid
tocopherol
solvent
carbonate
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Withdrawn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
EP97901601A
Other languages
German (de)
English (en)
Inventor
Hagen Jaedicke
Paul Grafen
Harald Laas
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.)
BASF SE
Original Assignee
BASF SE
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 SE filed Critical BASF SE
Publication of EP0882036A1 publication Critical patent/EP0882036A1/fr
Withdrawn legal-status Critical Current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 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
  • 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.
  • 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 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,
  • 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.
  • 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
  • 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
  • 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
  • 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 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.

Landscapes

  • 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.
EP97901601A 1996-01-29 1997-01-24 Procede de preparation de dl-alpha-tocopherol ou de dl-alpha-tocopherylacetate Withdrawn EP0882036A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19603142 1996-01-29
DE1996103142 DE19603142A1 (de) 1996-01-29 1996-01-29 Verfahren zur Herstellung von dl-alpha-Tocopherol oder dl-alpha-Tocopherylacetat
DE19617444 1996-05-02
DE1996117444 DE19617444A1 (de) 1996-05-02 1996-05-02 Verfahren zur Herstellung von dl-alpha-Tocopherol oder dl-alpha-Tocopherylacetat
PCT/EP1997/000324 WO1997028151A1 (fr) 1996-01-29 1997-01-24 PROCEDE DE PREPARATION DE DL-α-TOCOPHEROL OU DE DL-α-TOCOPHERYLACETATE

Publications (1)

Publication Number Publication Date
EP0882036A1 true EP0882036A1 (fr) 1998-12-09

Family

ID=26022450

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97901601A Withdrawn EP0882036A1 (fr) 1996-01-29 1997-01-24 Procede de preparation de dl-alpha-tocopherol ou de dl-alpha-tocopherylacetate

Country Status (5)

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

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
DE19704619A1 (de) * 1997-02-07 1998-08-13 Basf Ag Verfahren zur Herstellung von Tocopherylcarbonsäureestern oder Tocotrienylestern durch säurekatalysierte Umsetzung mit Carbonsäuren
ES2264230T3 (es) * 1998-04-06 2006-12-16 Dsm Ip Assets B.V. Procedimiento par ala obtencion de d,1-alfa-tocoferol, en un disolvente de carbonato y en presencia de un catalizador de acido conteniendo azufre.
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
IN188479B (fr) 1998-07-10 2002-09-28 Hoffmann La Roche
EP0970953B1 (fr) * 1998-07-10 2004-09-29 DSM IP Assets B.V. La préparation de l'alpha-tocophérol
ES2241718T3 (es) 2000-07-10 2005-11-01 Dsm Ip Assets B.V. Procedimiento de acilacion.
EP1172363B1 (fr) * 2000-07-10 2005-05-25 DSM IP Assets B.V. Procédé d'acylation
CN1205200C (zh) * 2000-11-22 2005-06-08 巴斯福股份公司 色原烷醇酯衍生物的连续酰化方法
JP4874236B2 (ja) * 2004-04-26 2012-02-15 ディーエスエム アイピー アセッツ ビー．ブイ． トコフェリルアシレートの製造方法
CN101006070B (zh) * 2004-08-19 2012-11-07 帝斯曼知识产权资产管理有限公司 包含维生素e和维生素e乙酸酯的混合物或产品流的整理方法
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
KR20210046014A (ko) 2018-08-17 2021-04-27 바스프 에스이 크로마놀 유도체의 합성
EP3837248B1 (fr) 2018-08-17 2024-07-24 Basf Se Synthèse de dérivés de chromanol et de 2-méthyl-1,4-naphtoquinone
EP3837247B1 (fr) 2018-08-17 2024-06-05 Basf Se Synthèse de dérivés de chromanol

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6035347B2 (ja) * 1976-07-26 1985-08-14 エーザイ株式会社 α−トコフエロ−ルの合成法
US4639533A (en) * 1982-07-29 1987-01-27 Basf Corporation Alpha tocopherol process
US5663376A (en) * 1994-07-27 1997-09-02 Eisai Co., Ltd. Process for the preparation of α-tocopherol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9728151A1 *

Also Published As

Publication number Publication date
RU2160258C2 (ru) 2000-12-10
CN1211243A (zh) 1999-03-17
JP2002502360A (ja) 2002-01-22
WO1997028151A1 (fr) 1997-08-07

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