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    A process for preparation of a glycidyl ether which is characrelized in reacting an epoxy compound of the formula wherein X is halogen or sulfonyloxy in the presence of a fluoride salt, with an alcohol. According to the above method, glycigyl ethers or their optically active compounds important as intermediates for synthesis of medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly optical purity.

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    A process for preparation of a glycidyl ether which is characrelized in reacting an epoxy compound of the formula wherein X is halogen or sulfonyloxy in the presence of a fluoride salt, with an alcohol. According to the above method, glycigyl ethers or their optically active compounds important as intermediates for synthesis of medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly optical purity.

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    © All Rights Reserved
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    12 views6 pages

    Us 6087512

    Uploaded by

    Lalit Modi
    A process for preparation of a glycidyl ether which is characrelized in reacting an epoxy compound of the formula wherein X is halogen or sulfonyloxy in the presence of a fluoride salt, with an alcohol. According to the above method, glycigyl ethers or their optically active compounds important as intermediates for synthesis of medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly optical purity.

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    United States Patent 1.) Furukawa et al. SOOGOSTSIZA, (1) Patent Number: 6,087,512 (45) Date of Patent: Jul. 11, 2000 (54) 175] 173) (21) (22 (86) (71 (30) (51) (52) (58) (56] PROCESS FOR PREPARATION OF GLYCIDYL ETHER Inventors: Yoshiro Furukawa, Osska; Kazuhiro Kitaori, tami; Tetsuya Yanagimoto; Masafumi Mikami, both of Amagasikis, Hiroshi Yoshimoto, Ibaraki; Junzo Otera, Okayama, all of Japan Assignee: Dalso Co, Ltd., Osaka, Japan Appl. Nos O4/47,715 PCT Filed p12, 1997 PCT Nos PCT/JP97/03221 §371 Date: Apr: 29, 1999 § 10%(e) Date: Apr. 29, 1999 PCT Pub, No: WO98/12186 PCT Pub, Date: Mar. 26, 1998 Foreign Application Priority Data 18,1996 [1P] Japan 240203 Int. COTD 301/28; CO7D 20328 US. Cl S49/517; 549/516 Fleld of Search 549/516, S17 References Cited FOREIGN PATENT DOCUMENTS 45485 1971991 European Pat. Of 102072 4/1989 Japan 12182 5/1980 Fapan 27887 11/1989 Japan 27800 11/1989 Japan 3.77886 4/1991 Japan 60374498 5/1904 Japan rrMT 7199S Jan OTHER PUBLICATION’ Shiratsuehi et al, Chom. Pharm Bull, “Synthesis and Activ. ity of Optical Isomers of Nipradilol,” 35 (9) 3691-3698 (987). Kawamura et al, Chem, Pharm. Bull, “An Efficient Syn: thesis of the Optical Isomers. of Nipradilol,” 38 (8) 2092-2096 (1990), Klunder et al. J Org. Chem, “Arenesultonate Derivatives ‘of Homochiral Glyeidol: Versatile Chiral Building Blocks for Organie Synthesis,” 54, 1295-1304 (198). Primary Examiner—Ba K. Trinh Attorney, Agent, or Firm—Tacobson, Price, Holman & Steen, PLLC 157] ABSTRACT. A process for preparation of a glycidyl ether which is ‘haracrelized in reacting an epoxy compound of the formula ‘wherein X is halogen or sulfonylo in the presence of a fuoride salt, with an alcohol, According to the above method, glycigyl ethers or ther optically active ‘compounds important as. intermediates for syuihesis of ‘medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly ‘optical purity. 9c ms, No Drawings 6,087,512 1 FOR PREPARATION OF LYCIDYL ETHER, This application is a 371 of PCT/IP97(3221, dated Sep, 12, 1997. 5 1, TECHNICAL FIELD The present invention relates to a process for preparation of glycidyl ethers and optical active compounds thereof imposiant as intermediates for syathesis of medicines and physiologically active compounds 2. BACKGROUND ART ‘Giyeidyl ethers are important intermediates for synthesis of many kinds of medicines. For example, so called Bereceptor blocking agenis which are often used as eircula ‘ory drugs, especially antihypertensive agents and antiae- ‘hythmic agents, are basically prepared om glycidyl ethers. ‘The glycidyl ethers have been prepared by reacting a corresponding alcohol with an epoxy compound, such as epichlorohydrin or glycidyl p-toluenesulfonate. The reaction of the alcohol with epichlorohydrin or glycidyl p-toluenesalfonate is caried out inthe presence of an alkali ‘metal base, sch as sodium hydride or sodium hydroxide, or an organie base, such a8 triethylamine or pyridine, o¢ ia the presence of catalyst such as & mineral acid (ey sulfuric acid) or Lewis acid (¢, tin tetrachloride) to prepare & Bechlore or tosyloxy-2-propanol derivative and i was eated wih 4 base fo prepare a glycidyl ether. However, in cease of carying out in the base in the former, the epoxy compound, such ss epichlorohydrin or glycidyl -oluenesulfonate must be used in excess and therefor, the reaction is not economical. In ease of using a strong base, such a8 sodium hydride or sodium hydoxide, the after lueatment, such as neutralization is necessary and it is troublesome. In ease of using sodium hydride there is & possibility of burning in the after-treatment. On the other hand, in ease of the latter in acidic conditions the weaction steps are many and the treatment is troublesome, Furthermore, in case of using an aryl derivative having substituent unstable in basic conditions, the yield is not good. By the way, glycidyl ethers have an asymmetric carbon tom and exis in optical isomers. Recently in developing the ‘medicines comprising optical isomers, each isomer is inves- tigated, Therefore, it becomes very important to establish & ‘method to prepare easily an optically active eompound with highly optical purity of these compounds. In onder 10 such problems, combinations of many kinds of bases Wi optically active epichlorohydrin, glycidyl poluenesilfonate, or glyeidyl m-nitrobenzenesilfonste hhave been investigated. These methods, for insance, ares eseribed in Japanese Patent Publication No. 1-121282, Tupanese Patent Publication No, 1-279890, Japanese Patent Publication No. 1-279887, European Patent No. 454385, “Japanese Patent Publication B No. 637449, Chem. Pharm. Bull, 35, 3691 (1987), Chem, Pharm. Bull, 38, 2092 ss (1990), 1. Org. Chem, 54, 1295 (1989) and so on, However, in all these’ methods, marked racemization ‘occurs on the reaction and the optical purity decreases. ‘Optical purity of an glycidyl ether prepared by reacting p-hycroxyphenslacetoamide and an optically active epichlo- rotycrin in sodium hydroxide as a base decreases 10 90% 8.0, and its not satisfactory ‘The present inventors cogaged extensively in solving above problems, and found to prepare easily and with good yield a glycidyl ether by reacting an epoxy compound and an Alcohol in the presence of a thuoride salt, Furthermore, when an optically active epoxy compound is used, the object 2 compound obtained is also optically active, and marked racemization does not oceue on the reaction, DISCLOSURE OF INVENTION ‘The present invention relates to a process for preparation fof a glycidyl ether of the formula woe o Wherein R is substituted oF unsubstituted alkyl, substituted ‘of unsubstituted aryl, or substituted or unsubstituted bets eroeyelic ring, ‘which is characterized i reacting an epoxy compound of the foermula a oe wherein X is halogen or sulfonyloxy group, with an aloohol of the formula Row o wherein R is as defined above, in the presence of a fuoride sal Examples of balogen shown by X ia the Formula (1) are chlorine atom, bromine atom and iodine atom, preferably chlorine atom and bromine atom. Examples of sulfonyloxy group shown by X in the formula (1) are preferably Substituted or unsubstituted alkylsulfonyloxy having 110 10 carbon atoms, such as methanesulfonyloxy or trifluoromethanesulfonyloxy, a substituted or unsubstituted arylsulfonyloxy, such as benzenesulfoayloxy, p-oluenesulfonyloxy or m-nitrobenzenesulfonyloxy. Examples ofthe epoxy compound ofthe formula (1) are epichlorohydrin, epibromohydrin, glycidyl rmethanesulfonate ulVeidyl wiluoromethanesulfonate, aly- cidyl ethanesulfonate, glycidyl propanesulfonate, glycidyl butanesulfonate, glycidyl phenylmethanesulfonate, glycidyl p-trifluoromethylbenzenesulfonate, glycidyl benzenesulfonate, giycidyl p-oluenesulfonat, glycidyl 2,4, 6-triisopropylbeazenesulfonate, glycidyl p-tert. butylbenzenesuifonate, slycidyl p-chiorobenzenesulfonate, glycidyl p-bromobenzenesulfonate, glycidyl p-iodobenzenesulfonate, glycidyl 24,5. trichlorobenzenesulfonate, glycidyl o-nitrobenzenesulfooste, glycidyl m-nitrobenzenesilfonate, glycidyl p-nitrobenzenesulfonate, glycidyl 2,4. dinitrobenzenesulfonate, glycidyl p-methoxybenzenesulfonate, glycidyl 4-chlora-3- hitrobenzenesulfonate, elycidyl I-naphthalenesullonate, glycidyl 2-naphthalenesulfoaate and so on. Glycidyl ‘m-nitrobenzenesulfonate, glycidyl p-toluenesulfonate and epichlorohydrin are preferably used among them Examples of the alcohol of the formula (2) are alkanols having 1 {0 10 carbon atoms, such as methanol, ethanol, propanol, butanol, isopropyl aleohol, isobutyl alcohol, t-butyl alcobol, sce-butyl aleobol and’ the like, alkanols substituted by a phenyl, such as benzyl alcohol, phenethyl alcohol, f-phenethylaicobol and the like, alkanols subsi- tuted by a phenyl having substituteni(s), such as 6,087,512 3 p-methoxybenzyl alcohol, p-nitrobenzyl aleobol and the like, Aromatic alonbols are also used, such as phenol and aromatic aleohols having substituent(). The substituents are ‘ot limited as far as they do not prevent this reaction, and jnclide saturated or uasatlated alkyl, such as met, ethyl, allyl and the Tike, alkyls having ether bonds), such as methoxymethyl, 2-methoxyethyl, allyloxymethyl, @-methoxycthoxy)methyl, 2-isopropoxyethoxy)metbyl and the lke, nitro, halogen, such as fluorine atom, chlorine tom, bromine stom and iodine atom, tilluoromethyl, alkoxys, such as methoxy, alyloxy, methoxymethoxy and the Tike, cyano, eyanomethyl, alkoxyearbonyis, such as methoxyearbonyl, ethoxyearbony! and the like, acyloxys, such as aceloxy and the like, amides, such as avetylamide and the like, carbamoyl, earbamoylmethy aklebyde,acyls, such as acetyl, beozoyl and the like. Furthermore, the substituent includes one and more substituents and may form a bridge, such as telramethylene or methylenediony withthe olber substituent, The substivents,alkyls may be unter substituted by another substituent ‘The above aromatic alcohol includes a polycyclic aro matic compound having hydroxy. Ahetcracyelie compound having hydroxy can be also used. Examples of them are polycyclic aromatic aleobols, sich as. c-naphthol, B- naphthol, 7-hydroxyindene and the like, heteroeyelie com luted by hydroxy, such as 3-hydeoxypyrisine, 3-hydroxytetrabydrofuran, 4-bydroxyindole, Sshyclroxyquinoline and so on. Preferable aleohols ofthe formula (2) are aromatic aleo- hols and heterocyelic compounds having hydroxy, espe= cially o-allylphenol, o-allyloxyphenol, 4-hydroxyindole, -2-isopropoxyethoxy)methylphenol, cenaphihol and eae bamoylmethy phenol ‘The amount ofthe alcohol of the formula (2) is 05 to 3 mole equivalent to epoxy compound (1), preferably OS to 1.2 mole equivalent, To use it more than 3 mole equivalent «does not aller, bu is not economical. On the other band, 10 tase it less than (1.5 mole equivalent causes to leave much Amount of an unreacted) epoxy compound and it is not eonnomica Preferable examples of the fluoride salts used in this reaction are quaternary ammonium fluorides, alkali metal Muorides and alkaline earth metal fluorides, especialy alkali ‘metal uorides and alkaline earth metal fluorides. These may be used alone or in combination of them and may be in Form being supported on a carter. Examples of the quatemary ammonium Muorides are tetramethylammonium fluoride, teteaethylammonium iluoride, tetrabutylammonium fluoride, tetraoctylammo- nium fluoride, benzyltrimethylammonium fluoride, ete. [Examples of the alkali metal fluorides are sodium fluoride, polassium fluoride and cesium fluoride. Examples of the Alkaline earth metal uorides are magnesium tfuoride and calcium fluoride. Examples of the carriers are Celite, lumina, silica gel, molecular sieves, its modified material And s0 6 “The amount of the Norge salt i 0.5 1 6 mole equivalent to epoxy compound of the formula (1), preferably, 0.9 to 6 ‘mole equivalent, To use it less than 0.5 mole equivalent does ‘ot make the reaction complete and to use more than 6 mole equivalent cause dificult to stir the reaction mixture. In case of using a fluoride salt together with an alkali metal hydro~ {gen cirhonate or carbonate mentioned below, the amount of the fluoride salt can reduced 10 0.05 mole equivalent to the epoxy compound. Even in case of using it les than 0.05 ‘mole equivalent the reaction proceeds, but it takes much hours in the reaction and is not practical 4 Examples of solvents used in this reaction are polar aprotic solvents, such as N,N-dimethylformamice, dimethyl Sillfoxide, sulforane, hexamethylphosphoramide and. the like, esters, such as ethyl acetate, Butyl acetate and the like, ethers, such as tetrahydrofuran, 1y-dioxane, 1,2. dimethoxyethane, t-butylmethy ether, diethyl ether and the like, Ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone andthe like nitrites, such as acetonitrile and the like, and a mixture of these solvents, Preferable ones are tetrahydrofuran, utylmethyl ether and actonirle, more preferably N,N-dimethylocmamide ‘The reaction proceeds without catalyst, but the eaction is, accelerated by sxlding NWN-dimethylaminopyridine, alkali ‘metal or alkaline earth meal halides, such a cesium fodide, potassium bromide, sodium bromide, magnesium bromide, Calcium bromide, potassium iodide, sodium iodide, magne sium iodide and caleium iodide, quaternary ammonium Salts, such a tetrabutylammonium Bride, teabutylammo- nium chloride, benzyltrimethylammonium bromide and the like, erown ethers, such as 18-Crown-6 and the like. The amount of the catalyst s0.1-50 mole percentage per alcohol @. The mechanism of the reaction is aot clear, but the vaction proceed in neutral conditions and it seems thatthe resulling acid is caught by a fluoride sal. Infact, when 9 week base, such as an alkali metal or alkaline eaih metal hhylrogen carbonate or earbonate as an acd trapping agent is added, the reaction is accelerated and the amount of the Auoride salt ean be reduced, Therefore, i is effective to add an alkali metal or alkaline earth metal hydrogen carbonate or carbonate, such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium jonate, calcium carbonate, magnesium carbonate, barium carbonate and the like, thereto, Its amount i ot limited, but usually 0.1 10 10 mole equivalent to alcohol of the formula (2), preferably 1 t0 3 mole equivalent is used “The reaction temperature i ~50° C. to boiling point ofthe solvent used, preferably =10 t0 100° C. In case of the {temperature being foo low, the reaction rate becomes low, and in case of the temperature being too high, degradation ofthe starting materials or product cecurs and the yield of the product decreases. Furthermore, whea an optically active epoxy compound is used, racemization occurs at the reaction temperature of more than 100° C. and therefore, such the high temperature is not preferable Regarding post treatment afler the reaction, insoluble materials are filtered off, water is added thereto and the ‘object compound is extrcted with an organic solvent, or lier the removal of insoluble materials, the filtrate may be subjected ©, after removal of the solvent, distillation, recrysallization, oF eoluma chromatography to prepare the ‘object compound. Therefore, these procedures are very simple and do n0t need any sch complex procedure as the Old procedure needs to react carefully the excess strong base with water or diluted hydrochloric aeid and make neutral: ination treatment and extraction, ‘According to the present invention, in case of using an optically active epoxy compound as a starting material, an optically active glycidyl ether is obtained. Incase of using fn epoxy compound with highly optical purity, marked racemization does not occur on the weaction thee is obtained 4 alyeidyl ether with highly optical purity. “The present invention is explained in detail by following examples, REFERENCE EXAMPLE 1 Preparation of Potassium Fluoride/Alumina Potassium fluoride (58.1 g) was dissolved in water (about 300/ml) and powdered alumina (aeutral, 100) were added 6,087,512 5 thereto, Water was distilled off in vacuo and the residue was dried ia vacuo, REFERENCE EXAMPLE 2 Preparation of Sodium Fluoride/Caleium Fluoride Sodium fluoride (42.0 g) was dissolved in water (about 300 mi) and calcium fluoride (78.1 g) was aed thereto and ‘mixture was sired wel. After removal of water in vacuo the residue was dried in vacuo, EXAMPLE 1 p-Hydoxyphieny! acvtamide (1 g) was dissolved in N.N-

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