Processes for Producing Alpha-Cyanohydrin Esters and Alpha-Hydroxy Acids

Europäisches Patentamt *EP000926134B1* (19) European Patent Office

Office européen des brevets (11) EP 0 926 134 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: C07C 253/08 of the grant of the patent: 17.09.2003 Bulletin 2003/38

(21) Application number: 98123461.0

(22) Date of filing: 11.12.1998

(54) Processes for producing alpha-cyanohydrin esters and alpha-hydroxy acids Verfahren zur Herstellung von Cyanhydricarbonsäureestern und alpha-Hydroxycarbonsäuren Procédé de préparation d’esters d’alpha-cyanohydrine et d’alpha-hydroxy acides

(84) Designated Contracting States: (74) Representative: Grünecker, Kinkeldey, DE FR GB Stockmair & Schwanhäusser Anwaltssozietät Maximilianstrasse 58 (30) Priority: 22.12.1997 JP 35339597 80538 München (DE)

(43) Date of publication of application: (56) References cited: 30.06.1999 Bulletin 1999/26 GB-A- 1 540 632 US-A- 4 113 763 US-A- 4 299 776 (73) Proprietor: Daicel Chemical Industries, Ltd. Osaka 590-8501 (JP) • MARCH, J.: "Advanced Organic Chemistry, 4th Edition" 1992 , JOHN WILEY & SONS , NEW (72) Inventors: YORK XP002097784 * page 397 - page 398 * • Ishii, Yasutaka Takatsuki.shi, Osaka 569-1112 (JP) Remarks: • Nakano, Tatsuya The file contains technical information submitted Himeji-shi, Hyogo 670-0094 (JP) after the application was filed and not included in this specification

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 926 134 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 0 926 134 B1 2

Description or a salt thereof. [0010] The inventors of the present invention did in- [0001] The present invention relates to processes for tensive investigation, and found that the reaction of an producing an α-cyanohydrin ester and an α-hydroxy ac- enol ester compound with a carbonyl compound and a id, or salts thereof using an enol ester compound, a car- 5 cyanogenation agent in the presence of a metal catalyst bonyl compound and a cyanogenation agent. provides the corresponding α-cyanohydrin ester in high [0002] α-hydroxy acids are very useful compounds as yield and that the corresponding α-hydroxy acid or a salt precise fine chemicals such as medicines and agricul- thereof can be efficiently derived from the α-cyanohy- tural chemicals, or intermediates thereof. drin ester by hydrolysis. The present invention was ac- [0003] As a process for producing α-hydroxy acids, 10 complished based on the above findings. there has been known a process which comprises re- [0011] That is to say, the present invention provides acting a carbonyl compound such as an aldehyde with a process for producing an α-cyanohydrin ester, which a cyanogenation agent such as hydrogen cyanide to comprises, in the presence of a metal catalyst, reacting produce the corresponding α-cyanohydrin compound, an enol ester compound shown by the formula (1): then hydrolyzing the obtained α-cyanohydrin com- 15 pound. In this process, however, since the cyanogenation reaction is reversible, it is generally difficult to obtain the corresponding α-cyanohydrin compound (particularly, an α-cyanohydrin compound derived from an aldehyde) in high yield. Moreover, since the obtained α- 20 cyanohydrin compound tends to decompose into the carbonyl compound and hydrogen cyanide by the hy- wherein R1 represents a hydrogen atom, a halo- drolysis, it is difficult to produce an α-hydroxy acid in gen atom, a substituted or unsubstituted alkyl group, a high yield. substituted or unsubstituted alkenyl group, a substituted [0004] US-A-4,113,763 discloses a process for mak- 25 or unsubstituted alkynyl group, a substituted or unsub- ing aromatic cyanohydrin esters which consists of add- stituted aryl group, a substituted or unsubstituted cy- ing a lower aliphatic acid anhydride under essentially cloalkyl group, or a substituted or unsubstituted hetero- anhydrous conditions to a mixture of an alkali metal cy- cyclic group; R2,R3, and R4 are the same or different anide and an aromatic aldehyde of the structure R-Ar- from each other and each represents a hydrogen atom CHO, where Ar is a member of the benzene or naphtha- 30 or an alkyl group having 1 to 5 carbon atoms; and R2, lene series and R is hydrogen or lower alkyl, said aro- R3, and R4, together with 1 or 2 adjacent carbon atoms, matic aldehyde and said cyanide being used in approx- may bond together to form a ring imate equimolar amounts and said anhydride being with a carbonyl compound shown by the formula used in a molar excess and controlling the exothermic (3): reaction to maintain a temperature between about 0° 35 and 50°C. [0005] US-A-4,299,776 discloses a process for preparing an insecticidal α-cyano-3-phenoxybenzyl ester which comprises reacting an acyl halide with 3-phe- noxybenzaldehyde and dissolved water-soluble cya- 40 nide salt in a mixture of substantially water-miscible aprotic solvent and water in a ratio of about 0.25 to 6. [0006] GB-A-1540632 discloses a process for the preparation of an ester, which comprises reacting a ben- wherein R7 and R8 are the same or different from zaldehyde with an acyl halide of the forumula R.CO.Hal 45 each other and each represents a hydrogen atom, a hal- (wherein Hal is bromine or chlorine) in the presence of ogen atom, a substituted or unsubstituted alkyl group, water, a water-soluble cyanide, a substantially water-im- a substituted or unsubstituted alkenyl group, a substi- miscible aprotic solvent and a phase transfer catalyst. tuted or unsubstituted alkynyl group, a substituted or un- [0007] It is an object of the present invention to pro- substituted aryl group, a substituted or unsubstituted cy- vide a process for producing a highly stable α-cyanohy- 50 cloalkyl group, or a substituted or unsubstituted hetero- drin ester useful as a precursor of an α-hydroxy acid in cyclic group; and R7 and R8, together with the adjacent high yield. carbon atom, may bond together to form a ring [0008] It is another object of the present invention to and a cyanogenation agent provide a process for producing an α-hydroxy acid or a to form an α-cyanohydrin ester shown by the for- salt thereof in high yield. 55 mula (4): [0009] A further object of the present invention is to provide a process for producing an α-hydroxy acid which is general-purpose and of broader applicability,

2 3 EP 0 926 134 B1 4

chromium Cr, molybdenum Mo, tungsten W ) , the group 7A elements (e.g., manganese Mn, technetium Tc, rhe- nium Re), the group 8 elements (e.g., iron Fe, ruthe- nium-Ru, osmium Os, cobalt Co, rhodium Rh, iridium Ir, 5 nickel Ni, osmium Os, cobalt Co, rhodium Rh, iridium Ir. nickel Ni, palladium Pd, platinum Pt), the group 1B elements (e.g., copper Cu, silver Ag, gold Au), and the wherein R1,R7. and R8 have the same meaning group 2B elements (e.g., zinc Zn, cadmium Cd) of the as defined above wherein said metal catalyst comprises Periodic Table of Elements. at least one element selected from the group consisting 10 [0016] Compounds comprising a metal element in- of the Group 3A elements, the Group 4A elements, the clude hydroxides, metal oxides (e.g., double oxides or group 5A elements, the Groups 6A elements, the Group oxygen acids, or salts thereof), organic acid salts, inor- 7A elements. the Group 8 elements, the Group 1B ele- ganic acid salts, halides, coordination compounds ments,the Group 2B elements, and the Group 3B ele- (complex) containing any of the metal elements men- ments of the Periodic Table of Elements. 15 tioned above, and polyacids (e.g., heteropolyacids and [0012] The present invention further provides a proc- isopolyacids), or salts thereof. As for the metal com- ess for producing an α-hydroxy acid or a salt thereof, pounds, the valence of their elements is not particularly which comprises restricted, and may be 2 to 6. preparing an α-cyanohydrin ester shown by the [0017] As the hydroxides, there may be exemplified 20 formula (4) by the above process, and Sm(OH)2, Sm(OH)3, Mn(OH)2, MnO(OH), Fe(OH)2,Fe hydrolysing the a-cyanohydrin ester shown by the (OH)3, and other corresponding metal hydroxides. As formula (4) to form an α-hydroxy acid or a salt thereof the metal oxides, there may be exemplified SmO2, shown by the formula (5): SmO3,TiO2, ZrO2,V2O3,V2O5, CrO, Cr2O3, MoO3, MnO, Mn3O4,Mn2O3, MnO2,Mn2O7, FeO, Fe2O3, 25 Fe3O4, RuO2, RuO4, CoO, CoO2,Co2O3, RhO2,Rh2O3, Cu2O3, and other corresponding metal oxides. As the double oxides or oxygen acids, or salts thereof, there may be exemplified MnAl2O4, MnTiO3, LaMnO3, . K2Mn2O5, CaO xMnOz ( x=0. 5, 1, 2, 3, 5), manganates 30 [e.g., manganates (V) such as Na3MnO4, and Ba3 [MnO4]2; manganates (VI) such as K2MnO4,Na2MnO4, and BaMnO4; and permanganates such as KMnO4, 7 8 wherein R and R have the same meaning as de- NaMnO4, LiMnO4.NH4MnO4, CsMnO4, AgMnO4,Ca fined above. (MnO4)2, Zn(MnO4)2, Ba(MnO4)2, Mg(MnO4)2, and Cd 35 [0013] Preferred embodiments of the invention are (MnO4)2; molybdic acid; tungstic acid; and other corre- set forth in the sub-claims. sponding metal double oxides or oxygen acids, or salts thereof. [Metal catalyst] [0018] As organic acid salts, there may be exemplified salts of organic acids such as organic carboxylic acid [0014] The metal catalyst includes simple substances 40 (e.g., monocarboxylic acids such as formic acid, acetic and compounds of specific metal elements, and may be acid, trichloroacetic acid, trifluoroacetic acid, propionic used singly or as a combination thereof. As the metal acid, butyric acid, valeric acid, naphthenic acid, and elements, there may be exemplified transition metal el- stearic acid; polycarboxylic acids such as oxalic acid ements, and the group 3B elements of the Periodic Ta- and maleic acid); hydroxycarboxylic acids; (e.g. , glycol- ble of Elements (e.g., boron B. aluminum Al). In the 45 ic acid, lactic acid, malic acid, tartaric acid, citric acid) present specification. boron B is also included as a met- thiocyanic acid, sulfonic acids (e.g., alkylsulfonic acids al element. such as methanesulfonic acid, trichloromethanesulfonic [0015] As the transition metal elements, there may be acid, trifluoromethanesulfonic acid, and ethanesulfonic exemplified the group 3A elements [rare earth metal el- acid; arylsulfonic acids such as benzenesulfonic acid ements (e.g., scandium Sc, yttrium Y, lanthanoid ele- 50 and p-toluenesulfonic acid). As inorganic acid salts, ments (lanthanum La, cerium Ce, praseodymium Pr, there may be exemplified nitrates, sulfates, phosphates, neodymium , Nd, promethium Pm, samarium Sm, euro- carbonates, and perchlorates. Concrete examples of or- pium Eu, gadolinium Gd, terbium Tb, dysprosium Dy, ganic acid salts or inorgnaic acid salt are samarium (II) holmium Ho, erbium Er, thulium Tm, ytterbium Yb, lute- acetate, samarium (III) acetate, cobalt acetate, manga- tium Lu), actinoid elements (e.g., actinium Ac)], the 55 nese acetate, cobalt propionate, manganese propion- group 4A elements (e.g., titanium Ti, zirconium Zr, haf- ate, cobalt naphthenate, manganese naphthenate, co- nium Hf), the group 5A elements (e.g., vanadium V, nio- balt stearate, manganese stearate, manganese thiocy- bium Nb, tantalum Ta), the group 6A elements (e..g, anate, samarium (II) trichloroacetate, samarium (III)

3 5 EP 0 926 134 B1 6 trichloroacetate, samarium (II) trifluoroacetate, samar- ano complexes (e.g., hexacyanomanganate (I), hexa- ium (III) trifluoroacetate, samarium (II) trifluorometh- cyanocuprate (II)), carbonyl complexes and cyclopen- anesulfonate (i.e., samarium (II) triflate), samarium (III) tadienyl complexes.(e.g., samallocene-type complexes trifluoromethanesulfonate (i.e., samarium (III) triflate), such as dicyclopentadienylsamarium (II), tricyclopenta- samarium (II) nitrate, cobalt nitrate, iron nitrate, manga- 5 dienylsamarium (III), dipentamethylcyclopentadienylsa- nese nitrate, nickel nitrate, copper nitrate, samarium (II) marium (II), and tripentamethylcyclopentadienylsamar- sulfate, cobalt sulfate, iron sulfate, manganese sulfate, ium(III); tricarbonylcyclopentadienylmanganese (I), bis- samarium (II) phosphate, cobalt phosphate, iron phos- cyclopentadienylmanganese (II), biscyclopentadienyli- phate, manganese phosphate, samarium (II) carbonate, ron (II), Fe(CO)5,Fe2(CO)9,Fe3(CO)12); nitrosyl com- 10 iron carbonate, manganese carbonate, iron perchlorate, pounds (e.g., Fe(NO)4,. Fe(CO)2 (NO)2); thiocyanato and other corresponding metal organic acid salts or in- complexes (e.g., thiocyanatocobalt, thiocyanatomanga- organic acid salts. nese, thiocyanatoiron), acetyl complexes (e.g., zirconyl [0019] Halides include fluorides, chlorides, bromides acetate ZrO(OAc)2, titanyl acetate. TiO(OAc)2, vanadyl and iodides. There may be mentioned, for example, hal- acetate VO(OAc)2 ), and other corresponding metal 15 ides such as chlorides [e.g., SmCl2, SmCl3, TiCl2, TiCl4, complexes. ZrCl2, ZrOCl2, VCl3, VOCl2, MoCl3, MnCl2, MnCl3, [0022] A polyacid (e.g., isopolyacid and heteropoly- FeCl2, FeCl3, RuCl3, CoCl2, RhCl2, RhCl3, NiCl2, PdCl2, acid) is usually at least one of, e.g., the group 5A ele- PtCl2, CuCl, CuCl2, AlCl3.], the corresponding fluorides, ments or the group 6A elements of the Periodic Table of bromides and iodides (e.g., SmF2, SmF3, SmBr2, Elements, such as V (vanadic acid), Mo (molybdic acid) 20 SmBr3, SmI2, SmI3, MnF2, MnBr2, MnF3, FeF2, FeF3, and W (tungstic acid). The central atom is not particu- FeBr2, FeBr3, FeI2, CuBr, CuBr2), double halides such larly restricted, and may be, e.g., Cu, Be, B, Al, Si, Ge, 1 1 1 1 1 as M MnCl3,M 2MnCl4,M 2MnCl5,M 2MnCl6 (M indi- Sn, Ti, Th, N, P, As, Sb, V, Nb, Ta, Cr, Mo, W, S, Se, Te, cates a monovalent metal), and other corresponding Mn, I, Fe, Co, Ni, Rh, Os, Ir, Pt. As concrete examples metal halides. of heteropolyacids or salts thereof, there may be men- [0020] As a ligand forming a complex, there may be 25 tioned phosphomolybdic acid, phosphotungstic acid; sil- exemplified hydroxo (OH), alkoxy groups such as meth- icomolybdic acid, silicotungstic acid, cobaltmolybdic ac- oxy, ethoxy, propoxy, and butoxy groups; acyl groups id, cobalttungstic acid, molybdenumtungstic acid, man- such as acetyl, and propionyl groups; alkoxycarbonyl ganesemolybdic acid, manganesetungstic acid, man- groups such as methoxycarbonyl (acetato) and ethoxy- ganesemolybdenumtungstic acid, vanadomolyb- carbonyl groups; acetylacetonato, cyclopentadienyl, 30 dophosphoric acid, phosphovanadomolybdic acid, C1-4alkyl-substituted dicyclopentadienyls (e.g., pen- manganesevanadiummolybdic acid, manganeseva- tamethylcyclopentadienyl); halogen atoms such as nadomolybdophosphoric acid, and salts thereof. chlorine and bromine; CO; CN; oxygen atom; H2O [0023] Further, as boron compounds, there may be (aquo); phosphorous compounds such as phosphines exemplified boric acids (e.g., orthoboric acid, methabo- (e.g., triarylphosphines such as triphenylphosphine); 35 ric acid, tetraboric acid); borates (e.g., nickel borate, oxygen-containing compounds such as tetrahydro- magnesium borate, manganese borate); boron oxides furan; and nitrogen-containing compounds such as NH3 such as B2O3, nitrogen-containing compounds such as (ammine), NO, NO2 (nitro), N03(nitrato), ethylenedi- borazane, borazen, borazine, and boron amide; halides amine, diethylenetriamine, pyridine, and phenanthro- such as BF3, BCl3, and tetrafluoroborate; and boric es- line. In a complex or a complex salt, the species of lig- 40 ters (e.g., methyl borate, phenyl borate). ands may be the same or different from each other, and [0024] The metal catalyst may be a homogeneous or one species or more than two species of ligands may heterogeneous system. Further, the catalyst may be a be coordinated therein. solid catalyst in which a catalytic component is support- [0021] As a preferable ligand in a complex, e.g., OH ed on a carrier. Porous carriers such as acitivated car- group. alkoxy groups, acyl groups, alkoxycarbonyl 45 bon, zeolites, silica, silica-alumina, bentonite are usual- groups, acetylacetonato, cyclopentadienyl, C1-2alkyl- ly employed as the carrier. The amount of the catalytic substituted cyclopentadienyls, halogen atoms, CO, CN, component supported on the carrier is 0.1 to 50 parts H2O (aquo), phosphorous compounds such as triphe- by weight, preferably 0.5 to 30 parts by weight, and more nylphosphine, oxygen-containing compounds such as preferably 1 to 20 parts by weight, relative to 100 parts tetrahydrofuran (THF), or nitrogen-containing com- 50 by weight of the carrier. pounds inclusive of NH3,NO2and NO3 are usually em- [0025] The catalyst is useful in producing an α-cyano- ployed. As a complex, there may be exemplified an hydrin ester derivative shown by the formula (4) by re- acetylacetonato complex (e.g., acetylacetonato-com- acting an enol ester compound shown by the formula plexes of e.g., Ce,Ti, Zr, V, Cr, Mo, Mn, Fe, Ru, Co, Ni, (1) with a carbonyl compound shown by the formula (3) 55 Cu, or Zn; titanylacetylacetonato complex TiO(AA)2; zir- and a cyanogenation agent. conylacetylacetonato complex ZrO(AA)2; vanady- lacetylacetonato complex VO(AA)2; diacetylacetona- tosamarium (II); triacetylacetonatosamarium (III)), cy-

4 7 EP 0 926 134 B1 8

[Enol ester compound (1)] stituted-oxycarbonyl groups (e.g., alkoxycarbonyl group, aryloxycarbonyl group), oxo group, carbamoyl [0026] In an enol ester compound shown by the for- group, substituted-carbamoyl groups, cyano group, ni- mula (1) (enol ester compound (1)), R1 represents group tro group, amino group, substituted-amino groups, sulfo hydrogen atom, halogen atoms, alkyl groups, alkenyl 5 group, aromatic hydrocarbon groups, heterocyclic groups, alkynyl group, aryl groups, cycloalkyl groups, groups, halogen atoms, alkyl groups, alkenyl groups, and heterocyclic groups. alkynyl groups, and cycloalkyl groups. [0027] The halogen atoms include iodine, bromine, [0033] Included as preferred R1 are hydrogen atom, chlorine, and fluorine. Alkyl groups include linear or C1-10alkyl groups (e.g., C1-6alkyl groups, particularly 10 branched chain alkyl groups having 1 to 20 carbon at- C1-4alkyl groups), C2-10alkenyl groups (e.g., C2-6alkenyl oms (preferably, alkyl groups having 1 to 10 carbon at- groups), C6-10aryl groups (e.g., phenyl group), and oms), such as-methyl, ethyl, propyl, isopropyl, butyl, iso- C3-10cycloalkyl groups (e.g., C5-8cycloalkyl groups). butyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, Among them, e.g., hydrogen atom, methyl group, ethyl undecyl, dodecyl, tetradecyl, and octadecyl groups. group, vinyl group, 2-propenyl group, and phenyl group Preferred alkyl groups are, e.g., lower alkyl groups hav- 15 are preferred as R1. ing 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms. [0034] In the formula (1). as alkyl groups having 1 to [0028] The alkenyl groups include alkenyl groups 5 carbon atoms represented by R2,R3, and R4, there having 2 to 20 carbon atoms (preferably alkenyl groups may be exemplified methyl, ethyl, propyl, isopropyl, having 2 to 10 carbon atoms, particularly about 2 to 6 butyl, isobutyl, and pentyl group. At least two groups of carbon atoms), such as vinyl, propenyl, 2-propenyl, 20 R2,R3, and R4, together with one or two adjacent carbon butenyl, pentenyl, octenyl, and dodecyl group. atoms, may bond together to form a ring. Examples of [0029] The alkynyl groups include alkynyl groups hav- such ring are cycloalkane rings or cycloalkene rings ing 2 to 20 carbon atoms (preferably alkynyl groups hav- such as cyclopropane ring, cyclobutane ring, cyclopen- ing 2 to 10 carbon atoms, particularly 2 to 6 carbon at- tane ring, cyclohexane ring, cyclohexene ring, and cy- oms), such as ethynyl, propynyl, and octhynyl group. 25 cloheptane ring. These are, e.g., 3 to 10 membered [0030] The aryl groups include aryl groups having 6 rings. 2 to 14 carbon atoms, such as phenyl group and naphthyl [0035] R is preferably a hydrogen atom or a C1-3alkyl group. Cycloalkyl groups include cycloalkyl groups hav- group, and more preferably a hydrogen atom. Each of 3 4 ing 3 to 10 carbon atoms, such as cyclopentyl, cy- R and R is preferably a hydrogen atom or a C1-3alkyl clohexyl, cycloheptyl, and cyclooctyl group. 30 group, and more preferably a hydrogen atom. [0031] Heterocycles corresponding to the heterocy- [0036] Preferred as an enol ester compound (1) are, clic groups include hyterocycles containing an oxygen e.g., vinyl formate, vinyl acetate, vinyl propionate, iso- atom as aheteroatom (e.g., 5-membered rings such as propenyl formate, isopropenyl acetate, and isopropenyl furan, oxazole, isooxazole, and tetrahydrofuran; propionate. 6-membered rings such as pyran; fused or condensed 35 rings such as benzofuran, isobenzofuran, dibenzofuran, [Carbonyl compound (3] xanthone, xanthene, chroman, isochroman, and chromene), heterocycles containing a sulfur atom as a [0037] The process of the present invention is appli- heteroatom (e.g., thiophene, thiazole, isothiazole, thia- cable to a wide range of carbonyl compounds regard- diazole, benzothiophene), heterocycles containing a ni- 40 less of being aldehydes or ketones. trogen atom as a heteroatom (e.g., 5-membered rings [0038] In a carbonyl compound shown by the formula such as pyrrole, pyrazole, imidazole, triazole, and pyr- (3) (carbonyl compound (3)), as atoms or organic rolidine; 6-membered rings such as pyridine, pyridazine, groups represented by R7 and R8, there may be men- pyrimidine, pyrazine, piperidine, and morpholine; fused tioned, e.g., the atoms and organic groups exemplified or condensed rings such as indole, indolene, isoindole, 45 in connection with R1. As a ring formed by R7 and R8 indazole, indoline, isoindoline, quinoline isoquinoline. bound together with the adjacent carbon atom, there quinolinequinoline quinoxaline, quinazoline, phthala- may be exemplified cycloalkane rings or cycloalkene zine, purine, carbazole, acridine, naphthoquinoline, rings such as cyclopropane ring, cyclobutane ring, cy- phenanthrodine, phenanthroline, naphthyridine, benzo- clopentane ring, cyclohexane ring, cyclohexene ring, quinoline, phenoxazine, phthalocyanlne. and anthracy- 50 cycloheptane ring, cyclooctane ring, cyclodecane ring, anine. and cyclododecane ring; and non-aromatic heterocy- [0032] R1, representing any of the alkyl groups, alke- cles containing 1 to 3 heteroatoms such as oxygen at- nyl groups, alkynyl groups, aryl groups, cycloalkyl om, sulfur atom and nitrogen atom. The ring is, e.g., 3 groups, and heterocyclic groups, may have a substitu- to 20 membered, preferably 3 to 16-membered, more ent. As a substituent, there may be exemplified hydroxyl 55 preferably 3 to 12-membered, and particularly 5 to group, mercapto group, carboxyl group, substituted-oxy 10-membered ring. groups (e.g., alkoxy group, aryloxy group), substituted- [0039] Among the carbonyl compounds (3), as con- thio groups (e.g., alkylthio group, arylthio group), sub- crete examples of an aldehyde, there may be exempli-

5 9 EP 0 926 134 B1 10 fied saturated aliphatic aldehydes having 2 to 20 carbon compounds, acyl cyanides, and cyanogen halides. Met- atoms (preferably, 2 to 10) such as acetoaldehyde, pro- al cyanides include, e.g., cyanides of alkaline metals, pionaldehyde, butanal, 2-methylpropanal, pentanal, such as sodium cyanide and potassium cyanide; cya- 3-methylbutanal, dimethylpropanal, hexanal, heptanal, nides of alkaline earth metals, such as calcium cyanide; octanal, decanal, dodecanal, and octadecanal; unsatu- 5 and cyanides of transition metals, such as copper cya- rated aliphatic aldehydes having 4 to 20 carbon atoms nide. Cyanohydrin compounds include a wide range of (preferably, 4 to 10) such as 3-butenal, and 3-octenal; α-cyanohydrin compounds corresponding to aliphatic, alicyclic aldehydes having 4 to 20 carbon atoms (pref- alicyclic, or aromatic aldehydes or ketones. As typical erably, 4 to 15) such as cyclopentanecarbaldehyde, cy- examples of α-cyanohydrin compounds, there may be clohexanecarbaldehyde, and cycloheptanecarbalde- 10 mentioned aliphatic α-cyanohydrins such as hydroxyac- hyde; aromatic aldehydes having 7 to 15 carbon atoms etonitrile, lactonitrile, acetone cyanohydrin, 2-hydroxyb- (preferably. 7 to 11) such as benzaldehyde, phenyla- utanenitrile, 2-hydroxy-4 -methylbutanenitrile. 2-hy- cetaldehyde, and 3-phenylpropanal; hetero cyclic alde- droxy-3-methylbutanenitrile, 2-hydroxy-3-butenenitrile, hydes having a 5- or 6-membered heterocycle having 1 2-hydroxypentanenitrile, 2-hydroxypentanenitrile, and to 3 heteroatoms of at least one kind selected from ox- 15 2-hydroxyoctanenitrile; alicyclic α-cyanohydrins such ygen atom, sulfur atom, and nitrogen atom or a con- as 2-hydroxy-cyclohexaneacetonitrile and cyclopen- densed heterocycle in which a benzene ring or the like tanone cyanohydrin; and aromatic α-cyanohydrins such is condensed with the 5- or 6-membered heterocycle, as mandelonitrile and 2-hydroxy-3-phenylbutanenitrile. such as 2-furancarbaldehyde. 2-furylacetoaldehyde, Acyl cyanides include aliphatic acyl cyanides such as 2-thiophenecarbaldehyde, 2-thienylacetoaldehyde, 20 acetyl cyanide and propionyl cyanide; and aromatic acyl 2-pyridinecarbaldehyde, 3-pyridinecarbaldehyde; 4-py- cyanides such as benzoyl cyanide. Cyanogen halides ridinecarbaldehyde, 2-pyridylacetoaldehyde, 3-2-pyri- include chlorocyanogen and bromocyanogen. dylacetoaldehyde, 4-pyridylacetoaldehyde, and [0043] Preferred as a cyanogenation agent are, e.g., 3-(2-quinolyl)propanal. hydrogen cyanide, metal cyanides, cyanohydrin com- [0040] Among the carbonyl compounds ( 3 ) , as ke- 25 pounds, and acyl cyanides. Among them, hydrogen cy- tones, there may be exemplified saturated aliphatic ke- anide, cyanides of alkaline metals, cyanohydrin com- tones having 3 to 15 carbon atoms (preferably, 3 to 10, pounds (especially, aliphatic α-cyanohydrins having 3 particularly 3 to 8) such as acetone, methyl ethyl ketone, to 8 carbon atoms), particularly α-cyanohydrins derived methyl propyl ketone, methyl isopropyl ketone, methyl from ketones are preferred. butyl ketone, methyl isobutyl ketone, methyl pentyl ke- 30 tone, and methyl isopentyl ketone;unsaturated aliphatic [production of α-cyanohydrin esters] ketones having 4 to 15 carbon atoms such as methyl vinyl keton, mesityl oxide, and methylheptenone; alicy- [0044] In the process for producing an α-cyanohydrin clic ketons having 3 to 20 carbon atoms (preferably, 3 ester, the enol ester compound (1) is reacted with the to 16) such as cyclobutanone, cyclopentanone, cy- 35 carbonyl compound (3) and a cyanogenation agent in clohexanone, and cyclododecanone; aromatic ketones the presence of a metal catalyst. having 8 to 18 carbon atoms (preferably, 8 to 15) such [0045] This reaction may be conducted in the ab- as acetophenone, propiophenone, butyrophenone, ve- sence of a solvent, but usually conducted in the pres- lerophenone, dibenzyl ketone, and 2-acetonaphthone; ence of a solvent. and heterocyclic ketones having a 5- or 6-membered 40 [0046] As the solvent, there may be exemplified aro- heterocycle having 1 to 3 heteroatoms of at least one matic hydrocarbons such as benzene, toluene, xylene, kind selected from oxygen atom, sulfur atom, and nitro- and ethylbenzene; hydrocarbon halides such as carbon gen atom, or a condensed heterocycle in which a ben- tetrachloride, chloroform, dichloromethane, and zene ring or the like is condensed with the 5- or 6-mem- 1,2-dichloroethane; aliphatic hydrocarbons such as bered heterocycle, such as acetothienone, 2-aceto- 45 pentane, hexane, heptane, and octane; alicyclic hydro- furon, 2-acetylpyridine, 3-acetylpyridine, 3-propionylpy- carbons such as cyclohexane and methylcyclohexane; ridine, 4-acetylpyridine, and 3-acetylquinoline. esters such as methyl acetate, ethyl acetate, isopropyl [0041] By varying the groups represented by R7 and acetate, butyl acetate, amyl acetate, cellosolve acetate, R8, various corresponding α-cyanohydrin esters (and and ethyl propionate; ethers such as diethyl ether, dib- various α-hydroxy acids and salts thereof) can be pro- 50 utyl ether, dioxane, and tetrahydrofuran; ketones such duced. as acetone and methylethylketone; and non-protonic polar solvents such as acetonitrile, N,N-dimethylforma- [Cyanogenation agent] mide, and dimethyl sulfoxide. [0047] The amount of the enol ester compound (1) is, [0042] As a cyanogenation agent, there may be em- 55 relative to 1 mole of the carbonyl compound (3), e.g.,0.5 ployed a conventional cyanogenation agent used for cy- to 5mole, preferably 0.8 to 4 mole, and more preferably anogenation reaction. For example, there may be men- 1 to 3 mole (particularly, 1.5 to 2.5 5 mole). The amount tioned hydrogen cyanide, metal cyanides, cyanohydrin of the cyanogenation agent used is, relative to 1 mole

6 11 EP 0 926 134 B1 12 of the carbonyl compound (3), e.g., not less than 0.8 monium salt thereof. These products can be converted mole (e.g., 0.8 to 5 mole), preferably 0.8 to 3 mole, and to basic salts of α-hydroxy acids by a conventional more preferably 0.9 to 1.5 mole. method. [0048] The amount of the metal catalyst used is, rel- [0058] The alkali hydrolysis is carried out in the pres- ative to 1 mole of the carbonyl compound (3), e.g., 0.001 5 ence of a base. As the base, there may be exemplified to 1 mole, preferably 0.01 to 0.5 mole, and more prefer- hydroxides of alkaline metals, such as lithium hydroxide, ably 0.05 to 0.2 mole. The reaction temperature is se- sodium hydroxide, and potassium hydroxide; hydrox- lected within the range not adversely affecting the reac- ides of alkaline earth matals, such as magnesium hy- tion. For example, the reaction temperature is 0 to droxide, calcium hydroxide, and barium hydroxide; car- 100°c, preferably 10 to 60°c, and more preferably 10 to 10 bonates of alkaline metals, such as sodium carbonate 40°C. and potassium carbonate; carbonates of alkaline earth [0049] The reaction may be carried out in a conven- metals such as magnesium carbonate; and hydrogen- tional manner such as batch system, semi-batch sys- carbonates of alkaline metals, such as sodium hydro- tem, and continuous system. As a result of the reaction gencarbonate and potassium hydrogencarbonate. above, an α-cyanohydrin ester derivative shown by the 15 [0059] The amount of the basis is, relative to 1 mole corresponding formula (4) is produced. After the com- of the α-cyanohydrin ester (4), not less than 1 mole, e. pletion of the reaction, a protonic compound such as wa- g., 1 to 10 mole, preferably, 1 to 5 mole, and more pref- ter may be added to the reaction system, if necessary. erably 2 to 3 mole. The amount of water is similar to [0050] Since this reaction proceeds irreversibly, an α- those exemplified in the paragraphs referring to acid hy- cyanohydrin ester (4) can be obtained in high yield. 20 drolysis, and the reaction may be conducted in the pres- [0051] The produced α-cyanohydrin ester (4) can be ence of any of the aforementioned organic solvents or separated and purified by a conventional separation and alcohols (e.g., methanol, ethanol). The reaction temper- purification method, e.g., filtration, concentration, ex- ature is, e.g.. 0 to 150°C, and preferably 10 to 110°C. traction, crystallization, recrystallization, column chro- [0060] Usually, the alkaline hydrolysis of the α-cyano- matography, or a combination of such methods. 25 hydrin ester (4) provides a basic salt of the correspond- [0052] Since the α-cyanohydrin ester (4) produced ing α-hydroxy acid. The basic salt of the α-hydroxy acid according to such process is different from α-cyanohy- can be converted to a free α-hydroxy acid or an acid salt drins, and unsusceptible to an elimination reaction such thereof by a conventional method. as de-hydrogen cyanidation ( elimination of hydrogen [0061] The hydrolysis reaction may be conducted by cyanide) under conditions of hydrolysis, it is useful as a 30 a conventional method such as batch system, semi- precursor of an α-hydroxy acid. batch system, and continuous system. After the com- pletion of the reaction, the pH is adjusted, if need be, [Production of an α-hydroxy acid or a salt thereof] and then the reaction product is easily separated and purified by a conventional separation method, e.g., fil- [0053] An α-hydroxy acid or a salt thereof can be ob- 35 tration, concentration, distillation, extraction, crystalliza- tained by hydrolyzing the α-cyanohydrin ester ( 4 ) ob- tion, recrystallization, column chromatography, and a tained by the process described above. combination of these methods. [0054] The hydrolysis can be conducted by a conven- [0062] According to the present invention, an α-cy- tional hydrolysis method, such as acid hydrolysis meth- anohydrin ester in high yield can be obtained from an od and alkali hydrolysis method. 40 enol ester compound, a carbonyl compound, and a cy- [0055] As acids that may be employed for acid hydrol- anogenation agent. ysis, there may be exemplified inorganic acids such as [0063] Moreover, by hydrolyzing the α-cyanohydrin hydrochloric acid, sulfuric acid, nitric acid, and phos- ester, the corresponding α-hydroxy acid or a salt thereof phoric acid; and sulfonic acids such as methanesulfonic can be produced in high yield. This process is of broader acid, ethanesulfonic acid, benzenesulfonic acid, and p- 45 applicability and general-purpose. toluenesulfonic acid. The amount of the acid is, e.g., [0064] The following examples describe the present 0.0001 to 10 mole, and preferably 0.01 to 4 mole relative invention in further detail. to 1 mole of the α-cyanohydrin ester (4). [0056] The amount of water is, relative to 1 mole of Example 1 the α-cyanohydrin ester (4), not less than 1 mole, and 50 suitably selected within the range of 1 to 100 mole. Hy- [0065] A mixture of 1 mmole of isopropenyl acetate, drolysis may be conducted in the presence of an organic 1 mmole of propanal, 1 mmole of acetone cyanohydrin, solvent, provided it doesn't affect the reaction. Exempli- 0.1 mmole of di(η5 pentamethylcyclopentadienyl) sa- fied as the organic solvent are the solvents mentioned marium [Cp*2Sm(THF)2], and 1 ml of toluene was stirred above. The reaction temperature is, e.g., 0 to 150°C, 55 at a temperature of 50°C for 5 hours. The analysis by a preferably 10 to 110°, and more preferably 40 to 100°C. gas chromatography revealed that 2-acetyloxybutanen- [0057] Usually, the acid hydrolysis of the α- cyanohy- itrile was formed in the reaction mixure in a 73% yield. drin ester (4) provides a free α-hydroxy acid or an am- The conversion of propanal was 79%.

7 13 EP 0 926 134 B1 14

Example 2 Example 9

[0066] The reaction was conducted in the same man- [0073] The reaction was conducted in the same manner as directed in Example 1 except for the use of 1 ner as Example 1 except for the use of 0.1 mmole of 5 5 mmol of butanal instead of propanal. The conversion of zirconyl chloride (ZrOCl2) instead of di(η -pentamethyl- butanal was 86%, and 2-acetyloxypentanenitrile was cyclopentadienyl)samarium [Cp*2Sm(THF)2]. The con- formed in an 81% yield. version of propanal was 77%, and 2-acetyloxybutanenitrile was formed in a 74% yield. Example 3 10 Example 10 [0067] The reaction was conducted in the same manner as Example 1 except for the use of 1 mmole of pen- [0074] The reaction was conducted in the same man- tanal instead of propanal. The conversion of pentanal ner as Example 1 except for the use of 0.1 mmole of 5 was 86%, and 2-acetyloxyhexanenitrile was formed in titanium tetrachloride (TiCl4) instead of di(η -pentame- 15 an 80% yield. thylcyclopentadienyl) samarium [Cp*2Sm(THF)2]. The conversion of propanal was 81%. and 2-acetyloxybu- Example 4 tanenitrile was formed in a 77%.

[0068] The reaction was conducted in the same man- Example 11 ner as Example 1 except for the use of 1 mmol of hex- 20 anal instead of propanal. The conversion of hexanal was [0075] The reaction was conducted in the same man- 86%, and 2-acetyloxyheptanenitrile was formed in an ner as Example 1 except for the use of 0.1 mmole of 5 81% yield. acetylacetonatozinc [Zn(AA)2] instead of di(η -pentamethylcyclopentadienyl)samarium [Cp*2Sm(ThF)2]. The Example 5 25 conversion of propanal was 66%, and 2-acetyloxybutanenitrile was formed in a 62% yield. [0069] The reaction was conducted in the same manner as Example 1 except for the use of 1 mmole of Example 12 3-methylbutanal instead of propanal. The conversion of 3-methylbutanal was 84%, and 2-acetyloxy-4-methyl- 30 [0076] The reaction was conducted in the same man- pentanenitrile was formed in a 79% yield. ner as Example 1 except for the use of 0.1 mmole of 5 copper chloride [Cu(Cl)2)] instead of di(η -pentamethyl- Example 6 cyclopentadienyl)samarium [Cp*2Sm(THF)2]. The conversion of propanal was 58%, and 2-acetyloxybutanen- [0070] The reaction was conducted in the same man- 35 itrile was formed in a 56% yield. ner as Example 1 except for the use of 1 mmole of 2-phenylacetaldehyde instead of propanal. The conver- Example 13 sion of 2-phenylacetaldehyde was 78%, and 2-acetyloxy-3-phenylpropanenitrile was formed in a 72% yield. [0077] The reaction was conduced in the same man- 40 ner as Example 1 except for the use of 0.1 mmole of Example 7 ferric chloride [Fe(Cl)3] instead of di(-η5-pentamethylcyclopentadienyl)samarium [Cp*2Sm(THF)2]. The con- [0071] The reaction was conducted in the same man- version of propanal was 55%, and 2-acetyloxybutanen- ner as Example 1 except for the use of 1 mmole of itrile was formed in a 53% yield. acetaldehyde instead of propanal. The conversion of 45 2-phenylacetaldehyde was 81%, and 2-acetyloxypro- Example 14 panenitrile was formed in a 74% yield. [0078] The reaction was conducted in the same man- Example 8 ner as Example 1 except for the use of 0.1 mmole of 50 5 vanadyl chloride (VOCl2) instead of di(η -pentamethyl- [0072] The reaction was conducted in the same man- cyclopentadienyl)samarium (Cp*2Sm(THF)2]. The con- ner as Example 1 except for the use of 0.1 mmole of version of propanal was 78%, and 2-acetyloxybutanen- 5 aluminium chloride anhydride (AlCl3) instead of di(η - itrile was formed in a 72% yield. pentamethylcyclopentadienyl)samarium [Cp*2Sm 55 (THF)2]. The conversion of propanal was 87%. and Example 15 2-acetyloxybutanenitrile was formed in an 81% yield. [0079] The reaction was conducted in the same manner as Example 1 except for the use of 0.1 mmole of-

8 15 EP 0 926 134 B1 16

5 molybdenum chloride [Mo(Cl)3] instead of di(η -pen- was stirred at 25°C for 15 hours. The analysis by gas tamethylcyclopentadienyl)samarium [Cp*2Sm( THF)2]. chromatography revealed that 2-acetyloxypropaneni- The conversion of propanal was 72%, and 2-acetyloxyb- trile was formed in the reaction mixture in a 74% yield. utanenitrile was formed in a 70% yield. 5 Example 22 Example 16 [0086] The reaction was conducted in the same man- [0080] The reaction was conducted in the same manner as Example 21 except for the use of 1 mmole of pro- ner as Example 2 except for the reaction temperature panal instead of acetaldehyde- 2-acetyloxybutanenitrile and the reaction time varied to 25°C and 3 hours, re- 10 was formed in a 87% yield. spectively. 2-acetyloxypentanenitrile was formed in a 56% yield. Example 23

Example 17 [0087] The reaction was conducted in the same man- 15 ner as Example 21 except for the use of 1 mmole of bu- [0081] The reaction was conducted in the same man- tanal instead of acetaldehyde. 2-acetyloxypentaneni- ner as Example 2 except for the reaction temperature trile was formed in a 84% yield. and reaction time varied to 25°C and 15 hours, respectively. 2-acetyloxypentanenitrile was formed in a 63% Example 24 yield. 20 [0088] The reaction was conducted in the same man- Example 18 ner as Example 21 except for the use of 1 mmole of 2-methylpropanal instead of acetaldehyde. 2-acetyloxy- [0082] The reaction was conducted in the same man- 3-methylbutanenitrile was formed in a 86% yield. ner as Example 2 except for the use of 0.1 mmole of di 25 5 (η -pentamethylcyclopentadienyl) ytterbium [Cp*2Yb Example 25 5 (THF )2] instead of di(η -pentamethylcyclopentadienyl) * samarium [Cp 2Sm(THF)2] and for the reaction temper- [0089] The reaction was conducted in the same man- ature and reaction time varied to 25°C and 3 hours, re- ner as Example 21 except for the use of 1 mmole of spectively. 2-acetyloxypentanenitrile was formed in a 30 3-methylbutanal instead of acetaldehyde. 2-acetyloxy- 21% yield. 4-methylpentanenitrile was formed in a 82% yield.

Example 19 Example 26

[0083] The reaction was conducted in the same man- 35 [0090] The reaction was conducted in the same manner as Example 2 except for the use of 0.1 mmole of ner as Example 21 except for the use of 1 mmole of 5 samarium isopropoxide [Sm(O-i-Pr)3] instead of di(η - 2,2-dimethylpropanal and 0.1 mmole of samarium iso- pentamethylcyclopentadienyl)samarium (Cp*2Sm propoxide [Sm(O-i-Pr)3] instead of acetaldehyde and di 5 (THF )2] and for the reaction temperature and reaction (η -pentamethylcyclopentadienyl)samarium (Cp*2Sm 40 time varied to 25°C and 3 hours, respectively. 2-acety- ( THF)2] respectively. 2-acetyloxy-3,3-dimethylbu- loxypentanenitrile was formed in a 61% yield. tanenitrile was formed in a 83% yield.

Example 20 Example 27

[0084] The reaction was conducted in the same man- 45 [0091] The reaction was conducted in the same manner as Example 2 except for the use of 0.1 mmole of ner as directed in Example 21 except for the use of 1 5 samarium isopropoxide [Sm(O-i-Pr)3] instead of di(η - mmole of cyclohexanecarbaldehyde instead of acetal- pentamethylcyclopentadienyl)samarium [Cp*2Sm dehyde. 2-acetyloxy-2-cyclohexylethanenitrile in a 90% (THF)2] and for the reaction temperature and reaction yield. time varied to 25°C and 15 hours, respectively. 2-acety- 50 loxypentanenitrile was formed in a 70% yield. Example 28

Example 21 [0092] The reaction was conducted in the same manner as Example 21 except for the use of 1 mmole of ben- [0085] A mixture of 2 mmole of isopropenyl acetate, 55 zaldehyde instead of acetaldehyde. 2-acetyloxy-3-phe- 1 mmole of acetaldehyde, 1 mmole of acetone cyano- nylethanenitrile was formed in a 49% yield. hydrin, 0.1 mmole of di(η5-pentamethylcyclopentadienyl)samarium. [Cp*2Sm(THF)2], and 1 ml of toluene

9 17 EP 0 926 134 B1 18

Example 29 Example 36

[0093] The reaction was conducted in the same man- [0100] The reaction was conducted in the same manner as Example 21 except for the use of 1 mmole of phe- ner as Example 32 except for the use of 10 mmole of nylacetaldehyde instead of acetaldehyde. 2-acetyloxy- 5 2-acetyloxy-4-methylpentanenitrile obtained in the 3-phenylpropanenitrile was formed in a 67% yield. same manner as Example 5 instead of 2-acetyloxybutanenitrile. 2-hydroxy-4methylpentanoic acid was Example 30 formed in an 81% yield.

[0094] The reaction was conducted in the same man- 10 Example 37 ner as Example 21 except for the use of 1 mmole of 2-furancarbaldehyde instead of acetaldehyde. 2-acety- [0101] The reaction was conducted in the same man- loxy-2-(2-furyl)ethanenitrile was formed in an 18% yield. ner as Example 32 except for the use of 10 mmole of 2-acetyloxy-3-phenylpropanenitrile obtained in the Example 31 15 same manner as Example 6 instead of 2-acetyloxybutanenitrile. 2-hydroxy-3-phenylpropionic acid was [0095] The reaction was conducted in the same man- formed in a 78% yield. ner as Example 21 except for the use of 1 mmole of cy- clohexanone instead of acetaldehyde and the reaction Example 38 temperature varied to 50°C. 1-acetyloxycyclohexanen- 20 itrile was formed in a 13% yield. [0102] The reaction was conducted in the same manner as Example 32 except for the use of 10 mmole of Example 32 2-acetyloxypropanenitrile obtained in the same manner as Example 7 instead of 2-acetyloxybutanenitrile. 2-hy- [0096] A mixture of 10 mmole of 2-acetyloxybutanen- 25 droxypropronic acid was formed in an 84% yield. itrile obtained in the same manner as Example 1, 20 mmole of potassium hydroxide, 5 ml of water and 10 ml of ethanol was stirred at 60°C for 3 hours. The analysis Claims of the reaction mixture by a high performance liquid chromatography revealed the formation of 2-hydroxyb- 30 1. A process for producing an α-cyanohydrin ester, utanoic acid in an 86% yield. which comprises, in the presence of a metal catalyst, Example 33 reacting an enol ester compound shown by the formula (1); [0097] The reaction was conducted in the same man- 35 ner as Example 32 except for the use of 10 mmole of 2-acetyloxypentanenitrile obtained in the same manner as Example 2 instead of 2-acetyloxybutanenitrile. 2-hy- droxypentanoic acid was formed in a 78% yield. 40 Example 34

[0098] The reaction was conducted in the same man- wherein R1 represents a hydrogen atom, a ner as Example 32 except for the use of 10 mmole of halogen atom, a substituted or unsubstituted alkyl 2-acetyloxyhexanenitrile obtained in the same ,manner 45 group, a substituted or unsubstituted alkenyl group, as Example 3 instead of 2-acetyloxybutanenitrile. 2-hy- a substituted or unsubstituted alkynyl group, a sub- droxyhexanoic acid was formed in an 82% yield. stituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or Example 35 unsubstituted heterocyclic group; R2,R3, and R4 50 are the same or different from each other and each [0099] The reaction was conducted in the same man- represents a hydrogen atom or an alkyl group hav- ner as Example 32 except for the use of 10 mmole of ing 1 to 5 carbon atoms; and R2 ,R3, and R4, to- 2-acetyloxyheptanenitrile obtained in the same manner gether with 1 or 2 adjacent carbon atoms, may bond as Example 4 instead of 2-acetyloxybutanenitrile. 2-hy- together to form a ring droxyheptanoic acid was formed in a 77% yield. 55 with a carbonyl compound shown by the formula (3):

10 19 EP 0 926 134 B1 20

agent, is a compound selected from hydrogen cyanide, cyanides of alkali metals and aliphatic α-cyanohydrins having 3 to 8 carbon atoms.

5 6. A process for producing an α-cyanohydrin ester according to Claim 1. wherein the amount of said enol ester compound (1), is to 5 mole relative to 1 mole wherein R7 and R8 are the same or different of said carbonyl compound (3). from each other and each represents a hydrogen atom, a halogen atom, a substituted or unsubstitut- 10 7. A process for producing an α-cyanohydrin ester ac- ed alkyl group, a substituted or unsubstituted alke- cording to Claim 1, wherein the amount of said cy- nyl group, a substituted or unsubstituted alkynyl anogenation agent is not less than 0.8 mole relative group, a substituted or unsubstituted aryl group, a to 1 mole,of said carbonyl compound (3). substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted-heterocyclic group; 15 8. A process for producing an α-cyanohydrin ester ac- and R7 and R8, together with the adjacent carbon cording to Claim 1, wherein the amount of said met- atom, may bond together to form a ring al catalyst is 0.001 to 1 mole relative to 1 mole of and a cyanogenation agent said carbonyl compound (3). to form an α-cyanohydrin ester shown by the formula (4): 20 9. A process for producing an α-cyanohydrin ester according to Claim 1, wherein R1 represents a hydrogen atom, a C1-6alkyl group, a C2-6alkenyl group, a 2 C6-10aryl group, or a C5-8cycloalkyl group; R represents a hydrogen atom or a methyl group; R3 and 25 R4 represent hydrogen atoms; R7 and R8 are the same or different from each other and each represents a hydrogen atom, a C1-6alkyl group, a C2-6alkenyl group, a C6-10aryl group, or a 7 8 C5-8cycloalkyl group; and R and R , together with wherein R1 ,R7, and R8 have the same mean- 30 the adjacent carbon atom, may bond together to ing as defined above, wherein said metal catalyst form a 3- to 16-membered ring. comprises at least one element selected from the group consisting of the Group 3A elements, the 10. A process for producing an α-cyanohydrin ester ac- Group 4A elements, the group 5A elements, the cording to Claim 9, wherein the amount of said enol Groups 6A elements, the Group 7A elements, the 35 ester compound (1) Group 8 elements, the Group 1B elements, the is 0.8 to 4 mole, the amount of said cyanogenation Group 2B elements, and the Group 3B elements of agent is 0.8 to 5 mole, and the amount of said metal the Periodic Table of Elements. catalyst is 0.01 to 0.5 mole, relative to 1 mole of said carbonyl compound (3). 2. A process for producing an α-cyanohydrin ester ac- 40 cording to Claim 1, wherein R1 is a group selected 11. A process for producing an α-hydroxy acid or a salt from hydrogen atom, C1-10alkyl groups, thereof, which comprises C2-10alkenyl groups, C3-10cycloalkyl groups, and preparing an α-cyanohydrin ester shown by C6-10aryl groups. the formula (4) by the process of any of claims 1 to 45 10, and 3. A process for producing an α-cyanohydrin ester ac- hydrolysing the α-cyanohydrin ester shown cording to claim 1, wherein R2,R3, and R4 are the by the formula (4) to form an α-hydroxy acid or a same or different from each other and each repre- salt thereof shown by the formula (5): sents a hydrogen atom or a C1-3alkyl group. 50 4. A process for producing an α-cyanihydrin ester according to. Claim 1, wherein said cyanogenation agent, is a cyanogen compound selected from hydrogen cyanide, metal cyanides, cyanohydrin compounds, and acyl cyanides. 55

5. A process for producing an α-cyanohydrin ester according to Claim 1, wherein said cyanogenation wherein R7 and R8 have the same meaning

11 21 EP 0 926 134 B1 22

as defined in claim 1 or 9

Patentansprüche 5 1. Verfahren zur Herstellung eines α-Cyanhydrine- sters, umfassend, in Gegenwart eines Metallkata- tysators, das Umsetzen einer Enolesterverbindung, dargestellt durch die Formel (1): worin R1,R7und R8 die gleiche Bedeutung wie zu- 10 vor beschrieben haben, wobei der Metalfkatalysa- tor mindestens ein Element umfasst, ausgewählt aus der Gruppe, bestehend aus den Elementen der Gruppe 3A, den Elementen der Gruppe 4A, den Elementen der Gruppe 5A, den Elementen der 15 Gruppe 6A, den Elementen der Gruppe 7A, den Elementen der Gruppe 8, den Elementen der Grup- pe 1 B, den Elementen der Gruppe 2B und den Ele- worin R1 ein Wasserstoffatom, ein Halogenatom, ei- menten der Gruppe 3B des Periodensystems der ne substituierte oder unsubstituierte Alkylgruppe, Elemente. eine substituierte oder unsubstituierte Alkenylgrup- 20 pe, eine substituierte oder unsubstituierte Alkinyl- 2. Verfahren zur Herstellung eines α-Cyanhydrine- gruppe, eine substituierte oder unsubstituierte Aryl- sters nach Anspruch 1, wobei R1 ein Wasserstoffa- gruppe, eine substituierte oder unsubstituierte Cy- tom, eine C1-10-Alkylgruppe, eine C2-10-Alkenyl- cloalkyl gruppe oder eine substituierte oder unsub- gruppe, eine C3-10Cycloalkylgruppe oder eine 25 stituierte heterocyclische Gruppe bedeutet, und C6-10-Arylgruppe bedeutet worin R2,R3und R4, die gleich oder verschieden sein können, ein Wasserstoffatom oder eine Al- 3. Verfahren zur Herstellung eines α-Cyanhydrine- kylgruppe mit 1 bis 5 Kohlenstoffatomen bedeuten, sters nach Anspruch 1, wobei R2,R3und R4, die wobei R2,R3und R4 zusammen mit 1 oder 2 be- gleich oder verschieden sein können, ein Wasser- 30 nachbarten Kohlenstoffatomen einen Ring bilden stoffatom oder eine C1-3-Alkylgruppe bedeuten. können, mit einer Carbonylverbindung, dargestellt durch die Formel (3): 4. Verfahren zur Herstellung eines α-Cyanhydrine- sters nach Anspruch 1, wobei das Mittel, das eine Cyanogruppe für die Umsetzung liefert, eine Cyan- 35 verbindung ist, ausgewählt aus Cyanwasserstoff, Metallcyaniden, Cyanhydrinverbindungen und Acylcyaniden.

5. Verfahren zur Herstellung eines a-Cyanhydrine- worin R7 und R8, die gleich oder verschieden sein 40 sters nach Anspruch 1, wobei das Mittel, das eine können, ein Wasserstoffatom, ein Halogenatom, ei- Cyanogruppe für die Umsetzung liefert, eine Ver- ne substituierte oder unsubstituierte Alkylgruppe, bindung ist, ausgewählt aus Cyanwasserstoff, Cy- eine substituierte oder unsubstituierte Alkenylgrup- aniden von Alkalimetallen und aliphatischen a-Cy- pe, eine substituierte oder unsubstituierte Alkinyl- anhydrinverbindungen mit 3 bis 8 Kohlenstoffato- gruppe, eine substituierte oder unsubstituierte Aryl- 45 men. gruppe, eine substituierte oder unsubstituierte Cy- cloalkylgruppe oder eine substituierte oder unsub- 6. Verfahren zur Herstellung eines α-Cyanhydrine- stituierte heterocyclische Gruppe bedeuten, wobei sters nach Anspruch 1, wobei die Menge an Enole- R7 und R8 zusammen mit dem benachbarten Koh- sterverbindung (1) im Bereich von 0,5 bis 5 Mol lenstoffatom einen Ring bilden können, 50 liegt, bezogen auf 1 Mol der Carbonylverbindung und (3). einem Mittel, das eine Cyariogruppe für die Umset- zung liefert, um einen α-Cyanhydrinester zu erhal- 7. Verfahren zur Herstellung eines α-Cyanhydrine- ten, dargestellt durch die Formel (4): sters nach Anspruch 1, wobei die Menge an Mittel, 55 das eine Cyanogruppe für die Umsetzung liefert, nicht weniger als 0,8 Mol beträgt, bezogen auf 1 Mol der Carbonylverbindung (3).

12 23 EP 0 926 134 B1 24

8. Verfahren zur Herstellung eines α-Cyanhydrine- sters nach Anspruch 1, wobei die Menge an Metall- katalysator im Bereich von 0,001 bis 1 Mol liegt, bezogen auf 1 Mol der Carbonylverbindung (3). 5 9. Verfahren zur Herstellung eines α-Cyanhydrine- sters nach Anspruch 1, wobei R1 ein Wasserstoffa- tom, eine C1-6Alkylgruppe, eine C2-6-Alkenylgrup- 1 pe, eine C6-10-Arylgruppe oder eine C5-8-Cycloal- dans laquelle R représente l'atome d'hydro- kylgruppe bedeutet, R2 bedeutet ein Wasserstoffa- 10 gène, un atome d'halogène, un radical alkyle subs- tom oder eine Methylgruppe, R3 und R4 bedeuten titué ou non substitué, un radical alkényle substitué Wasserstoffatome, und R7 und R8, die gleich oder ou non substitué, un radical alkynyle substitué ou verschieden sein können, bedeuten ein Wasser- non substitué, un radical aryle substitué ou non stoffatom, eine C1-6-Alkylgruppe, eine c2-6-Alkenyl- substitué, un radical cycloalkyle substitué ou non 15 gruppe,eine C6-10-Arylgruppe oder eine C5-8-Cyclo- substitué, ou un radical hétérocyclique substitué ou alkylgruppe, wobei R7 und R8 zusammen mit dem non substitué ; R2,R3,etR4sont identiques ou dif- benachbarten Kohlenstoffatom einen 3- bis férents l'un de l'autre et chacun représente l'atome 16-gliedrigen Ring bilden können. d'hydrogène ou un radical alkyle possédant de 1 à 5 atomes de carbone ; et R2,R3,etR4, pris ensem- 10. Verfahren zur Herstellung eines α-Cyanhydrine- 20 ble avec 1 ou 2 atomes de carbone adjacents, peu- sters nach Anspruch 9, wobei die Menge an Enole- vent se lier ensemble pour former un cycle sterverbindung (1) im Bereich von 0,8 bis 4 Mol avec un composé carbonylé représenté par la liegt, wobei die Menge an Mittel, das eine Cyano- formule (3): gruppe für die Umsetzung liefert, im Bereich von 0,8 bis 5 Mol liegt, und wobei die Menge an Metallka- 25 talysator im Bereich von 0,01 bis 0,5 Mol liegt, bezogen auf 1 Mol der Carbonylverbindung (3).

11. Verfahren zur Herstellung einer α-Hydroxysäure oder eines Salzes davon, umfassend das Herstel- 30 dans laquelle R7 et R8 sont identiques ou dif- len eines α-Cyanhydrinesters, dargestellt durch die férents l'un de l'autre et chacun représente l'atome Formel (4), unter Anwendung des Verfahrens nach d'hydrogène, un atome d'halogène, un radical alk- einem der Ansprüche 1 bis 10 und das Hydrolysie- yle substitué ou non substitué, un radical alkényle ren des α-Cyanhydrinesters, dargestellt durch die substitué ou non substitué, un radical alkynyle Formel (4), um eine α-Hydroxysäure oder ein Salz 35 substitué ou non substitué, un radical aryle substi- davon zu erhalten, dargestellt durch die Formel (5): tué ou non substitué, un radical cycloalkyle substi- tué ou non substitué, ou un radical hétérocyclique substitué ou non substitué ; et R7 et R8 pris ensemble avec l'atome de carbone adjacent, peuvent se 40 lier ensemble pour former un cycle et un agent de cyanogénation pour former un ester d'α-cyanohydrine repré- senté par la formule (4) :

45 worin R7 und R8 die gleiche Bedeutung wie in An- spruch 1 oder 9 haben.

Revendications 50

1. Procédé de préparation d'un ester d'α-cyanohydrine, qui comprend, en présence d'un catalyseur mé- dans laquelle R1,R7,etR8possèdent la mê- tallique, me signification que celle définie ci-dessus, procé- la réaction d'un composé ester d'énol repré- 55 dé dans lequel ledit catalyseur métallique com- senté par la formule (1): prend au moins un élément choisi dans le groupe composé des éléments du Groupe 3A, des élé- ments du Groupe 4A, des éléments du Groupe 5A,

13 25 EP 0 926 134 B1 26

des éléments du Groupe 6A, des éléments du Grou- alkyle en C1-6, un radical alkényle en C2-6, un radi- pe 7A, des éléments du Groupe 8, des éléments du cal aryle en C6-10, ou un radical cycloalkyle en C5-8; Groupe 1B, des éléments du Groupe 2B, et des élé- et R7 et R8, pris ensemble avec l'atome de carbone ments du Groupe 3B du Tableau Périodique des adjacent, peuvent se lier ensemble pour former un Éléments. 5 noyau comprenant de 3 à 16 chaînons.

2. Procédé de préparation d'un ester d'α-cyanohydri- 10. Procédé de préparation d'un ester d'α-cyanohydrine selon la revendication 1, dans lequel R1 repré- ne selon la revendication 9, dans lequel la quantité sente un radical choisi parmi l'atome d'hydrogène, dudit composé ester d'énol (1) est de 0,8 à 4 moles, 10 des radicaux alkyle en C1-10, des radicaux alkényle la quantité dudit agent de cyanogénation est de 0,8 en C2-10, des radicaux cycloalkyle en C3-10,etdes à 5 moles, et la quantité dudit catalyseur métallique radicaux aryle en C6-10. est de 0,01 à 0,5 mole, par rapport à 1 mole dudit composé carbonylé (3). 3. Procédé de préparation d'un ester d'α-cyanohydrine selon la revendication 1, dans lequel R2,R3,et 15 11. Procédé de préparation d'un a-hydroxy acide ou R4 sont identiques ou différents l'un de l'autre et d'un sel de celui-ci, qui comprend chacun représente l'atome d'hydrogène ou un radi- la préparation d'un ester d'α-cyanohydrine re- cal alkyle en C1-3. présenté par la formule (4) par le procédé selon l'une quelconque des revendications 1 à 10, et 4. Procédé de préparation d'un ester d'α-cyanohydri- 20 l'hydrolyse de l'ester d'α-cyanohydrine repré- ne selon la revendication 1, dans lequel ledit agent senté par la formule (4) pour former un α-hydroxy de cyanogénation est un composé cyanogène choi- acide ou un sel de celui-ci représenté par la formule si parmi le cyanure d'hydrogène, des cyanures mé- (5) : talliques, des composés cyanohydrines, et des cyanures d'acyle. 25

5. Procédé de préparation d'un ester d'α-cyanohydrine selon la revendication 1, dans lequel ledit agent de cyanogénation est un composé choisi parmi le cyanure d'hydrogène, des cyanures de métaux al- 30 calins et des α-cyanohydrines aliphatiques possé- dant 3 à 8 atomes de carbone. dans laquelle R7 et R8 possèdent la même si- 6. Procédé de préparation d'un ester d'α-cyanohydri- gnification que celle définie dans la revendication 1 ne selon la revendication 1, dans lequel la quantité 35 ou 9. dudit composé ester d'énol (1) est de 0,5 à 5 moles par rapport à 1 mole dudit composé carbonylé (3).

7. Procédé de préparation d'un ester d'α-cyanohydrine selon la revendication 1, dans lequel la quantité 40 dudit agent de cyanogénation n'est pas inférieure à 0,8 mole par rapport à 1 mole dudit composé car- bonylé (3).

8. Procédé de préparation d'un ester d'α-cyanohydri- 45 ne selon la revendication 1, dans lequel la quantité dudit catalyseur métallique est de 0,001 à 1 mole par rapport à 1 mole dudit composé carbonylé (3).

9. Procédé de préparation d'un ester d'α-cyanohydri- 50 ne selon la revendication 1, dans lequel R1 repré- sente l'atome d'hydrogène, un radical alkyle en C1-6, un radical alkényle en C2-6, un radical aryle en 2 C6-10, ou un radical cycloalkyle en C5-8;R repré- sente l'atome d'hydrogène ou le radical méthyle ; 55 R3 et R4 représentent des atomes d'hydrogène ; R7 et R8 sont identiques ou différents l'un de l'autre et chacun représente l'atome d'hydrogène, un radical