WO2013035899A1 - Procédé de préparation de 5-hydroxy-1,3-dioxane et procédé de préparation de trimères de glycérol ramifiés au moyen du 5-hydroxy-1,3-dioxane en tant que matière première - Google Patents

Procédé de préparation de 5-hydroxy-1,3-dioxane et procédé de préparation de trimères de glycérol ramifiés au moyen du 5-hydroxy-1,3-dioxane en tant que matière première Download PDF

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WO2013035899A1
WO2013035899A1 PCT/KR2011/006631 KR2011006631W WO2013035899A1 WO 2013035899 A1 WO2013035899 A1 WO 2013035899A1 KR 2011006631 W KR2011006631 W KR 2011006631W WO 2013035899 A1 WO2013035899 A1 WO 2013035899A1
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dioxane
hydroxy
glycerol
mixture
reaction
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PCT/KR2011/006631
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English (en)
Korean (ko)
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네모토히사오
하토리하츠히코
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주식회사 코리아테크노에이전시
토쿠시마 대학
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Priority to PCT/KR2011/006631 priority Critical patent/WO2013035899A1/fr
Publication of WO2013035899A1 publication Critical patent/WO2013035899A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

  • the present invention is a glycerol form which is a mixture of 5-hydroxy-1, 3-dioxane ( ⁇ , ⁇ -isomer) and 4-hydroxymethyl-1, 3-dioxolane ( ⁇ , ⁇ -isomer)
  • a method of producing 5-hydroxy-1,3-dioxane with high purity by using horses as a raw material, and preferably adding glycerol, and using 5-hydroxy-1,3-dioxane as raw materials A method for producing a branched glycerol trimer.
  • branched glycerol oligo glycerol
  • BGL branched oligo glycerol
  • the glycerol formal obtained from the glycerol and formaldehyde is a mixture of the ⁇ , ⁇ -isomer and 4-hydroxymethyl-1, 3-dioxolane which is the ⁇ , ⁇ -isomer represented by the following formula (2). .
  • glycerol formal available from Tokyo Chemical Industry Co., Ltd. is a mixture of ⁇ , ⁇ -isomers and ⁇ , ⁇ -isomers. Because the properties of the two isomers are similar, it is very difficult to separate and purify them.
  • Patent Document 1 International Publication No. 2004/029018
  • Patent Document 2 International Publication No. 2005/023844
  • Patent Document 3 International Publication No. 2008/093655
  • Non-Patent Document 1 Jean-Louis Gras, Robert Nouguier, Mohammed Mchich, Tetrahedron Letters 28 (52), 1987, P6601-6604
  • Non-Patent Document 2 Merck Index (14) 4485
  • Glycerol formal obtained from glycerol and formaldehyde is suitable as a raw material for branched glycerol because of its low cost, but ⁇ and ⁇ -isomers contained in glycerol formal cannot be used as raw materials for branched glycerol.
  • a mixture of ⁇ , ⁇ '-isomers and ⁇ , ⁇ -isomers of glycerol formal is used as a raw material to produce ⁇ , ⁇ '-isomers of high purity, and ⁇ , ⁇ '-isomers of the high purity are used as raw materials. It was mentioned as a subject to manufacture branched glycerol trimer as a subject.
  • the step of obtaining a mixture having a higher ratio of 5-hydroxy-1,3-dioxane than the starting material is characterized in that the addition of 0.1 to 5 moles of glycerol per 1 mole of the starting material mixture do.
  • the present invention provides a method for producing a formal group-protected branched glycerol trimer represented by the formula (3), characterized in that the 5-hydroxy-1, 3-dioxane as a raw material.
  • the present invention provides a formal group-protected branched glycerol trimer [Formula 3] prepared using the 5-hydroxy-1, 3-dioxane as a raw material.
  • the present invention provides a method for producing a branched glycerol trimer protected with acetonide group, characterized in that the formally protected branched glycerol trimer is used as a raw material.
  • the (alpha), (beta) -isomer contained in glycerol formal can be converted into the (alpha), (alpha)-isomer.
  • isomerization reaction is carried out by adding glycerol, it is possible to obtain high concentrations of the ⁇ and ⁇ '-isomers in high yield while suppressing the formation of by-products.
  • the ⁇ , ⁇ '-isomer, pivaloyl and trityl bodies can be separated by distillation or extraction. Therefore, it is possible to manufacture high purity ⁇ , ⁇ -isomers easily and inexpensively with high efficiency. It is also possible to produce branched glycerol trimers using the above high-purity ⁇ and ⁇ -isomers as raw materials.
  • FIG. 1 is a schematic diagram briefly showing a pibylation method.
  • FIG. 2 is a schematic diagram briefly showing a tritylation method.
  • FIG. 3 is a diagram showing 1 H-NMR results of a mixture of (a) a ratio of 1,3-mG and 1,2-mG of 99.8: 0.2, and (b) a trityl mixture.
  • available glycerol formals include 5-hydroxy-1, 3-dioxane ( ⁇ , ⁇ '-isomer) and 4-hydroxymethyl-1, 3-dioxolane ( ⁇ , ⁇ -Isomer) is contained at 55: 45-60: 40 (mass ratio).
  • the ⁇ , ⁇ -isomer and the ⁇ , ⁇ -isomer have a boiling point difference of 0.3 ° C. at normal pressure, for example, and it is difficult to separate them by distillation. Therefore, the present inventors performed some treatment operation
  • a mixture of 5-hydroxy-1, 3-dioxane, 4-hydroxymethyl-1, 3-dioxolane is used as a starting material, and concentrated sulfuric acid is added as an acid catalyst at 40 to 100 ° C. The process of heating is performed.
  • heating time is not specifically limited, Usually, they are several hours-about several ten hours. In the Example mentioned later, since the isomerization rate improved in order of 3 hours, 6 hours, and 18 hours, it is preferable to heat for 6 hours or more.
  • Concentrated sulfuric acid which is an acid catalyst, can be used in a concentration of 90% or more (mass). However, as described above, water may inhibit isomerization, and therefore, 98% of concentrated sulfuric acid having the highest concentration among the concentrated sulfuric acid on the market. Preference is given to using.
  • the amount of concentrated sulfuric acid is preferably about 0.01% to 8% of the raw material mass, and more preferably about 0.2% to 5%. After completion
  • glycerol formal i.e., a mixture of 5-hydroxy-1, 3-dioxane and 4-hydroxymethyl-1, 3-dioxolane as starting materials. You may use a mixture with commercially available glycerol formal.
  • 1,4-dioxane is hygroscopic, but in the reaction of the present invention, the presence of water is not preferable, and it was also confirmed in the experimental example described later that the dioxane dried was higher than the wet one, and therefore, the dioxane was dried. It is preferable to use oxane.
  • glycerol In the isomerization reaction of this invention, it is preferable to add glycerol.
  • glycerol When glycerol is added, it is because the present inventors discovered that the effect of raising the ratio of alpha, alpha -isomer is large and the yield is further improved. The reason for this is as follows.
  • the said problem was solved by adding an glycerol and performing an isomerization reaction, and succeeded in raising the yield of the (alpha), (alpha) '-isomer.
  • dilute sulfuric acid functions well as an acid, but as mentioned above, since the presence of water encourages unwanted side reactions, it cannot be said to be an acid suitable for the isomerization reaction in the present invention. If dilute sulfuric acid does not contain water, it can be said to be an acid suitable for the isomerization reaction in the present invention, but it does not exist in the world.
  • the isomerization reaction was performed in high yield in a novel concept of adding glycerol to the reaction system instead of water, rather than a chemical species of dilute sulfuric acid containing no water.
  • glycerol formal is ⁇ , ⁇ '-isomer and ⁇ , ⁇ -isomer can be assumed to be a mixture of 55:45 to 60:40 (mass ratio).
  • the reaction time is short, a large amount of formaldehyde and glycerin remain, and the long-term reaction can be expected to decrease the total chemical yield as a result of the side reaction.
  • a side reaction called multimerization in order to suppress the side reactions, the polyhydric alcohols constituting the ⁇ and ⁇ -isomers and What is necessary is just to add the same alcohol, and came to this invention. This technical idea is a technical idea which was not seen before.
  • the pivaloylated or tritylated ⁇ , ⁇ -isomer becomes insoluble in water due to the high fat solubility of pivaloyl group or trityl group, so that only the ⁇ , ⁇ -isomer is transferred to the aqueous layer by an extraction operation.
  • Monolithic or tritylated ⁇ , ⁇ -isomers are separated and purified by transition to an organic solvent (e.g., hexane, ether, and the like, more preferably a lower polar solvent, hexane, benzene, toluene, preferably hexane). It is also possible.
  • the compound which can be pivalylated and tritylation for example, pivaloyl chloride and trityl chloride (all three places) is used.
  • Pivaloyl chloride or trityl chloride (all two places) hardly reacts with the ⁇ and ⁇ -isomers and binds only to the hydroxyl groups of the ⁇ and ⁇ -isomers.
  • pivaloyl chloride or trityl chloride is added to a mixture of the ⁇ and ⁇ -isomers of the glycerol formal with the ⁇ and ⁇ -isomers.
  • the baloyl- ⁇ and ⁇ -isomers have a boiling point of about 110 ° C. at 8 mmHg (10.7 hPa). Therefore, by performing vacuum distillation after pivaloylation and tritylation, it becomes possible to isolate (alpha), (alpha)-isomer from a reaction product.
  • the pressure reduction degree at the time of vacuum distillation is not limited to the above, There is no restriction as long as it can isolate
  • an extraction operation using water and an organic solvent described above may be used.
  • Pivaloylation is halogenated, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene, in the presence of organic bases such as N-methylpiperidine, pyridine, 4-pyrrolidinopyridine and the like. Hydrocarbons can be performed as a solvent.
  • reaction temperature about -10 degreeC-about 30 degreeC are preferable, and reaction time is not specifically limited. After the reaction, it is preferable to neutralize the reaction product as appropriate.
  • Tritylation is necessary in the presence of an organic base such as N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, 2, 4, 6-collidine, or an inorganic base such as sodium hydrogencarbonate in addition to these. Therefore, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene, can be performed as a solvent.
  • reaction temperature about -10 degreeC-about 30 degreeC are preferable, and reaction time is not specifically limited. After the reaction, it is preferable to neutralize the reaction product as appropriate.
  • the (alpha), (alpha)-isomer of this glycerol formal can be said to be a compound which protected glycerol with a formal group. Therefore, by using ⁇ and ⁇ -isomers of glycerol formal as raw materials and appropriately reacting with epihalohydrin such as epichlorohydrin, a branched glycerol trimer protected by a formal group can be produced.
  • This trimerization reaction can be performed, for example in presence of a base, such as potassium hydroxide, and a correlation transfer catalyst, such as tetrabutylammonium bromide.
  • the product is preferably purified by silica gel column chromatography or the like.
  • the branched glycerol trimer protected with the acetonide group can also be manufactured using the said branched glycerol trimer protected by the said formal group.
  • Acetonide by removing a formal protecting group of the branched glycerol trimer with, for example, an acid such as hydrochloric acid, and then neutralizing and reacting a known compound such as 2,2-dimethoxypropane for acetonitrile after neutralization.
  • Branched glycerol trimers protected with groups can be obtained.
  • acetonitrile may use a general acid catalyst, it is more preferable to carry out in presence of solid acid catalysts, such as "Amberlyst (R) 15" (made by Rohm and Haas). Of course, other protecting groups may be attached.
  • the said patent document 1-3 describes the synthesis method of BGL in detail, and the (alpha), (alpha) '-isomer of the said glycerol formal is suitable as a raw material of these BGL.
  • the isomerization reaction was performed by the same method as the above except having changed the mixing ratio of a solvent, glycerol amount, heating temperature, reaction time, and a raw material mixture as shown in Table 1. The results are shown in Table 1.
  • the ratios of ⁇ -pivaloyl- ⁇ , ⁇ '-isomers and ⁇ '-pivaloyl- ⁇ , ⁇ -isomers obtained in 17 were obtained by depivaloylation from a 9:91 mixture. , ⁇ -isomer ratio was prepared by mixing a 9:91 mixture and the commercially available 57:43 mixture.
  • glycerol formal (1 equivalent), glycerol (1 equivalent), and 1,4-dioxane (3-6 M) are added to the reaction vessel and installed in a mantle heater, equipped with a mechanical stirrer and a thermometer, and argon ( Ar) was replaced with gas and stirred at 200 rpm. Thereafter, the mixture was added dropwise with H 2 SO 4 (1-0.355 mol%), and the temperature was slowly increased until the internal temperature became 60 ° C, and the ratio of 1,3-mG and 1,2-mG was> 70: Stir at 500 rpm until ⁇ 30 (see Scheme 4 below). When the desired ratio was reached, the speed was lowered to 200 rpm and cooled to room temperature.
  • the aqueous layer was once more added hexane, separated into an aqueous layer and a hexane layer, and the hexane layer was combined with the hexane layer.
  • the combined hexane layer was dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure, and the remaining product was a mixture of Piv-1, 3-mG, Piv-1, 2-mG.
  • the water in the aqueous layer was added with ethanol and distilled under reduced pressure to obtain a residue.
  • the residue was diluted with dichloromethane, dried over anhydrous MgSO 4 , filtered, and the solvent was distilled off.
  • TrCl Of 10 equivalents of TrCl was added to the reaction, and the reaction was stopped by stirring until no CO 2 gas was generated.
  • the mixed solution was separated into an aqueous layer and a dichloromethane layer.
  • CH 2 Cl 2 of the organic layer was distilled off under reduced pressure, and the residue was added to the aqueous layer.
  • the aqueous layer was extracted by adding hexane, and separated into an aqueous layer and an organic layer A.
  • the aqueous layer is extracted once more with hexane and separated into aqueous layer and organic layer B.
  • Ethanol for azeotropic addition to the aqueous layer was added, and the residue was distilled under reduced pressure to obtain a residue.
  • the crude product was diluted with dichloromethane, dried over anhydrous MgSO 4 , filtered, and solvent distilled off to obtain residue A.
  • the water and ethanol recovered by the above-mentioned pressure distillation were distilled under reduced pressure again to obtain a residue B.
  • the residue A and the residue B were combined and subjected to simple distillation (66 ° C./8 mmHg) to obtain 1,3-mG having a purity> 99.5% or more.
  • the organic layer A and the organic layer B were combined, dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure, and the remaining product was a mixture of Tr-1, 3-mG, Tr-1, 2-mG (see Scheme 7 below).
  • the final product was analyzed using 1 H-NMR. The results are shown in FIG.
  • TrCl Of 10 equivalents of TrCl was added to the reaction and stirred until no CO 2 gas was generated.
  • the mixed solution was separated into an aqueous layer and a dichloromethane layer.
  • CH 2 Cl 2 of the organic layer was distilled off under reduced pressure, and the residue was added to the aqueous layer.
  • the aqueous layer was extracted by adding hexane, and separated into an aqueous layer and an organic layer A.
  • the aqueous layer was extracted once more with hexane, and separated into an aqueous layer and an organic layer B.
  • Ethanol for azeotropic addition to the aqueous layer was added and distillation under reduced pressure was carried out to obtain a residue.
  • the product was diluted with dichloromethane, dried over anhydrous MgSO 4 , filtered, and solvent distilled off to obtain residue A.
  • the water and ethanol recovered at reduced pressure were distilled off under reduced pressure again to obtain residue B.
  • the residue A and the residue B were combined and subjected to simple distillation (66 ° C./8 mmHg) to obtain 1,3-mG of purity> 99.5% or more.
  • the organic layer A and the organic layer B were combined, dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure, and the remaining product was a mixture of Tr-1, 3-mG, Tr-1, and 2-mG (see Scheme 8 below).
  • the 5-hydroxy-1, 3-dioxane ( ⁇ , ⁇ '-isomer) of glycerol formal obtained in the present invention is bound to a stability or water solubility improvement technique such as a physiologically active polypeptide, a biphilic substance or a hydrophobic substance. It is useful as a raw material of branched glycerol applicable to the technique used as a drug carrier, the technique which improves the water solubility of a fibrate type antihyperlipidemic compound, and makes it easy to use as a medicine.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de 5-hydroxy-1,3-dioxane (isomère α, α' du glycérol formal) qui convient très bien en tant que matière première pour un glycérol ramifié, et concerne plus particulièrement un procédé de préparation de 5-hydroxy-1,3-dioxane, comprenant les étapes consistant à : utiliser, en tant que matière de départ, un mélange de 5-hydroxy-1,3-dioxane et de 4-hydroxyméthyl-1,3-dioxolane, de préférence ajouter du glycérol, puis chauffer le mélange à 40 à 100 °C en présence d'un acide sulfurique concentré en tant que catalyseur acide pour obtenir un mélange dans lequel la proportion de 5-hydroxy-1,3-dioxane est supérieure à celle dans la matière de départ ; et faire réagir du chlorure de pivaloyle et du chlorure de trityle avec le mélange contenant la proportion accrue de 5-hydroxy-1,3-dioxane, pour effectuer ainsi la séparation et la purification du 5-hydroxy-1,3-dioxane n'ayant pas réagi par distillation ou extraction.
PCT/KR2011/006631 2011-09-07 2011-09-07 Procédé de préparation de 5-hydroxy-1,3-dioxane et procédé de préparation de trimères de glycérol ramifiés au moyen du 5-hydroxy-1,3-dioxane en tant que matière première WO2013035899A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105473347A (zh) * 2013-09-09 2016-04-06 住友橡胶工业株式会社 充气轮胎
WO2020255741A1 (fr) * 2019-06-17 2020-12-24 有限会社ケミカル電子 Agent de traitement de surface métallique hydrophile

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Publication number Priority date Publication date Assignee Title
EP1666486A1 (fr) * 2003-09-03 2006-06-07 Kyowa Hakko Kogyo Co., Ltd Compose modifie a l'aide d'un derive de glycerol
WO2008093655A1 (fr) * 2007-01-30 2008-08-07 The University Of Tokushima Composé polyol et agent pharmaceutique
WO2010022263A2 (fr) * 2008-08-20 2010-02-25 Futurefuel Chemical Company Procédé de préparation de glycérol formal

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP1666486A1 (fr) * 2003-09-03 2006-06-07 Kyowa Hakko Kogyo Co., Ltd Compose modifie a l'aide d'un derive de glycerol
WO2008093655A1 (fr) * 2007-01-30 2008-08-07 The University Of Tokushima Composé polyol et agent pharmaceutique
WO2010022263A2 (fr) * 2008-08-20 2010-02-25 Futurefuel Chemical Company Procédé de préparation de glycérol formal

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HISAO NEMOTO ET AL.: "An efficient and practical method for the preparation of a brached oligoglycerol with acetonide protection groups", CHEMISTRY LETTERS, vol. 39, no. 8, 2010, pages 856 - 857 *
HISAO NEMOTO ET AL.: "Synthesis of Branched Heptaglycerol Bearing Eight Hydroxyl Groups with Four Cyclic Protecting Groups", SYNLETT, no. 13, 2007, pages 2091 - 2095 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105473347A (zh) * 2013-09-09 2016-04-06 住友橡胶工业株式会社 充气轮胎
WO2020255741A1 (fr) * 2019-06-17 2020-12-24 有限会社ケミカル電子 Agent de traitement de surface métallique hydrophile
TWI728843B (zh) * 2019-06-17 2021-05-21 日商化學電子有限公司 親水性金屬表面處理劑、將金屬的表面加以處理之方法、保護分支型甘油衍生物、以及用以製造保護分支型甘油衍生物之方法
US11124881B2 (en) 2019-06-17 2021-09-21 Chemical Denshi Co., Ltd. Hydrophilic metal surface treatment agent

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