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WO2004054966A1 - Procede pour produire des cyanhydrines optiquement actives et leurs acides mandeliques correspondants - Google Patents

Procede pour produire des cyanhydrines optiquement actives et leurs acides mandeliques correspondants Download PDF

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Publication number
WO2004054966A1
WO2004054966A1 PCT/EP2003/013636 EP0313636W WO2004054966A1 WO 2004054966 A1 WO2004054966 A1 WO 2004054966A1 EP 0313636 W EP0313636 W EP 0313636W WO 2004054966 A1 WO2004054966 A1 WO 2004054966A1
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WO
WIPO (PCT)
Prior art keywords
aldehyde
acid
mol
salen
optically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2003/013636
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German (de)
English (en)
Inventor
Marion Korb
Rainer Fell
Bettina Kirschbaum
Daniel Decker
Monika Kratzer
Georg Bieder
Walter Hahn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clariant Produkte Deutschland GmbH
Original Assignee
Clariant GmbH
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Filing date
Publication date
Application filed by Clariant GmbH filed Critical Clariant GmbH
Publication of WO2004054966A1 publication Critical patent/WO2004054966A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B01J31/2243—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/50—Complexes comprising metals of Group V (VA or VB) as the central metal
    • B01J2531/56—Vanadium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to a process for the production of optically active cyanohydrins by means of an optically active vanadyl catalyst in a liquid-liquid 2-phase system.
  • Optically active cyanohydrins and their secondary products e.g. optically active ⁇ -hydroxycarboxylic acids serve as building blocks for the production of biologically active substances, e.g. used in the pharmaceutical or agro industry. Cyanohydrins are accessible through various chemical reactions, such as in Top. Curr. Chem. 1999, 200, 193-226.
  • a synthesis possibility for optically active cyanohydrins consists in aldehydes in the presence of molecules with "CN" groups (HCN, MCN with M: alkali metal, trimethylsilyl cyanide - also known as TMSCN, cyanohydrins such as acetone cyanohydrin) and an optically active catalyst in (S) - or (R) - to convert cyanohydrins (Compr. Asymmetrie Catal. I-Ill, 1999 (2), Chap. 28).
  • Vanadyl salen complexes catalyze the reaction of aldehydes with trimethylsilyl cyanide in principle with higher enantioselectivity than the corresponding titanium salen catalysts (YN Beiokon, M. North, T. Parsons, Org. Lett. 2000, 2, 1617-1619.)
  • TMSCN TMSCN
  • M. North and Y. N. Beiokon describe the preparation of O-acetylated cyanohydrins in a solid-liquid 2-phase mixture (M. North, Y. N. Beiokon, WO02 / 10095) using an alkali metal cyanide in the form of its salt.
  • the use of free HCN gives poor ee values under the same conditions (0-29%; M. North, Y. N. Beiokon, Chem. Commun. 2002, 244-245.).
  • a CN source such as trimethylsilyl cyanide is not very suitable for industrial use because it is expensive and also causes large amounts of silicon-containing waste.
  • the implementation of low temperatures such as -80 ° C in technical applications is also expensive and not very practical. Solid alkali metal cyanides are difficult to handle on an industrial scale for safety reasons.
  • the task was to find a method that would overcome the difficulties associated with the reagents commonly used in the literature and overcomes restrictions with regard to the cyanide source to be used and the reaction temperature and, moreover, also permits the use of pure liquid hydrocyanic acid or an aqueous solution of alkali metal cyanides in a simple manner, without requiring great effort, even technically.
  • the present invention solves this problem and relates to processes for the preparation of optically active cyanohydrins by reacting an aldehyde with a cyanide source in the presence of an optically active vanadyl catalyst which contains a salen ligand at a temperature in the range from 0 to 60 ° C., the reaction in a liquid-liquid 2-phase system, consisting of an organic solvent and an aqueous phase, and the ratio of salen ligand: vanadium (IV) in the catalyst is in the range from 1.4: 1 to 10: 1
  • the invention relates to the preparation of cyanohydrins of the formula (II)
  • optically active center * has the absolute configuration (R) or (S)
  • R represents an optionally branched alkyl, alkenyl or alkynyl radical of the chain length Ci to C 2 o, in particular Ci to Cs, or a radical of the formula (lla)
  • aldehydes of the formula (Ia) are used.
  • X preferably represents F, Cl, Br, I, OH, 0 (-C 4 alkyl), OCOCH 3 , NHCOCH 3 , N0 2 or CC 4 alkyl and Y and Z each represent H. or X and Y each for H and Z for OH or X for H and Y and Z each for OH.
  • hydrocyanic acid hydrocyanic acid stabilized with acid or an aqueous solution of a metal cyanide, preferably an alkali cyanide, in particular a sodium or potassium cyanide, such as, for example, commercially available aqueous sodium / potassium cyanide solutions with a cyanide content of 13-14%, can be used as the cyanide source.
  • a metal cyanide preferably an alkali cyanide, in particular a sodium or potassium cyanide, such as, for example, commercially available aqueous sodium / potassium cyanide solutions with a cyanide content of 13-14%
  • the cyanohydrin contained in the reaction mixture can optionally be converted directly into the corresponding ⁇ -hydroxycarboxylic acid by hydrolysis.
  • One advantage of the process according to the invention is that it is possible not only to use the aldehydes in comparatively low concentrations, for example 0.1 mol aldehyde / liter, as was customary hitherto, but also to use them Reaction with considerably higher aldehyde concentrations, for example 2.0 mol aldehyde / liter up to 10 mol aldehyde / liter, preferably 2 to 4 mol aldehyde / liter. Accordingly, the space-time yield for stereoselective cyanohydrin reactions is unusually high.
  • the reaction with the cyanide source is carried out in a liquid-liquid 2-phase mixture.
  • organic solvents or solvent mixtures which are inert under the conditions of the reaction are suitable as organic solvents.
  • C ⁇ - Cio aromatic and C1-C 10 aliphatic, optionally halogenated hydrocarbons or solvent mixtures thereof, and aliphatic ethers with 1-5 carbon atoms per alkyl radical, or cyclic ethers with 4-5 carbon atoms in the ring are particularly suitable as organic solvents.
  • aqueous solutions of acids are suitable as the aqueous solvent.
  • the concentration of the acid in the aqueous solution is preferably 0 to 85%, in particular 0 to 60%.
  • an 85% acid concentration would correspond to the use of pure phosphoric acid, a 37% acid concentration to the use of concentrated hydrochloric acid.
  • Buffers are generally used to prepare 1% solutions.
  • the volume ratio of organic to aqueous phase is usually in the range from 20: 1 to 1:20, in particular in the range from 10: 1 to 1:10.
  • 0.8 to 10.0, in particular 1.0 to 5.0, preferably 1.1 to 3.5, particularly preferably 1.3 to 2.3 mol of cyanide source are used per mol of aldehyde of the formula (I).
  • the process according to the invention is carried out at a temperature of 0 to 60 ° C., preferably 10 to 50 ° C., in particular 20 to 40 ° C.
  • Suitable catalysts are vanadyl-salen complexes consisting of salen ligands of the general formula (III) and vanadium in the oxidation stage (IV).
  • the radicals R, R 'and R "of the salen ligand of the general formula (III) can independently of one another be hydrogen, branched or unbranched C 1 -C 10 alkyl radicals, in particular a methyl or tert-butyl radical, or a group 0 (C * ⁇ -C 4 alkyl), in particular a methoxy group or halogens, in particular Cl, a substituted aryl group, in particular a phenyl group, or - (CH 2 ) m - where m can be an integer between 1 and 8.
  • the ratio of salen ligand: vanadium (IV) in the catalyst is in the range from 1.4: 1 to 10: 1, preferably in the range from 1.4: 1 to 5: 1, in particular from 1.4: 1 to 3: 1 ,
  • Such catalysts are described in the priority German patent application DE-A-101 31 811.1 (internal number 2001 DE309).
  • the catalyst is prepared by reacting vanadyl sulfate with 1, 4 to 10, in particular with 1, 4 to 5 equivalents of the corresponding salen ligand.
  • the catalysts contain salen ligands of the formula (III) and vanadium in the oxidation stage (IV) and are preferably synthesized in alcohols in a heterogeneous reaction environment or in a chlorinated hydrocarbon / alcohol mixture in a heterogeneous reaction environment.
  • Catalyst mixed with the aldehyde in a suitable organic solvent 0.000005 to 0.05 equivalents of catalyst are preferred
  • aqueous solution of a mineral acid or an aqueous solution of an organic compound with acidic functional groups are then added.
  • the ratio of organic solvent to aqueous phase is 20: 1 to 1:20, preferably 15: 1 to 1:15, in particular 8: 1 to 1: 8.
  • the pH of the aqueous phase is 1.5 to 7, preferably 2 to 6, particularly preferably 2.5 to 5.5. If necessary, the pH must be adjusted to a value in the range from pH 1.5 to 7, preferably 2 to 6, particularly preferably 2.5 to 5.5 using an alkali salt solution. This is often achieved by adding alkali cyanide solution or HCN.
  • a buffer solution such as, for example, phosphoric acid / phosphate buffer, acetic acid / acetate buffer, citric acid / citrate buffer or glutamic acid / glutamate buffer, which has a pH between 1, 5 and 7, is preferred 2 to 6, particularly preferably 2.5 to 5.5, is possible.
  • the reaction is carried out at 0 to 60 ° C., in particular at 10 to 50 ° C., preferably at 20 to 40 ° C. In many cases it has proven useful to let the reaction proceed at room temperature.
  • the aldehyde of the formula (I) is added to the reaction mixture in a concentration of 0.1 to 10.0, in particular 0.5 to 5.0, preferably 1.0 to 4.5 mol, of aldehyde / liter. In a large number of cases, it has proven useful to carry out the reaction with HCN or the aqueous alkali metal cyanide solution with an aldehyde concentration of 2.0 to 4.0 mol / liter.
  • the optically active cyanohydrin can be isolated from the reaction mixture and, if necessary, cleaned.
  • the optically active cyanohydrin e.g. crystallize in the cold, preferably at temperatures in the range from -20 ° C to 10 ° C.
  • the optically active cyanohydrin if appropriate in the form of the reaction mixture, can also be converted, for example by acid hydrolysis, into the corresponding optically active ⁇ -hydroxycarboxylic acid.
  • Strong acidic acids such as conc. HCI or aqueous sulfuric acid.
  • the aqueous phase must be separated from the reaction mixture before the hydrolysis of the cyanohydrin.
  • the aqueous phase in which the acid is contained, and the organic phase, in which the optically active cyanohydrin is located, must be thoroughly mixed.
  • the process according to the invention surprisingly enables aldehydes to be converted into the optically active cyanohydrins of both the (S) and the (R) series in a liquid-liquid 2-phase system with high conversions and good ee values.
  • substrates which are particularly difficult for, for example, enzymatic processes, such as benzaldehydes substituted in the 2-position, for example 2-chlorobenzaldehyde, can optionally be successfully converted to the corresponding optically active (S) - or (R) -cyanohydrins using the process according to the invention. Examples:
  • a VO-salen complex is used to produce a complex of salen ligands of the formula (III) and vanadium in the oxidation state (IV), such as, for example, B. understood vanadyl (IV) sulfate.
  • the present VaO-Salen complex can be used in the form of the present crude product or, if desired, after purification by chromatography.
  • the aqueous phase is separated from the reaction mixture. Then 92.0 g of conc. Hydrochloric acid is added and the hydrolysis mixture is heated to 60 ° C. for 6 hours with vigorous stirring.
  • Examples 8-9 were carried out analogously to Example 7, in accordance with the information in Table 1.
  • Examples 11 to 18 were carried out analogously to Example 10, in accordance with the information in Table 2.
  • the reaction mixture is stirred at room temperature for 24 hours. According to the GC, the conversion is 99%; 74% ee for the (S) -2-chloromandelic acid cyanohydrin.
  • the reaction mixture is stirred at room temperature for 24 hours. According to the GC, the turnover is 29%; 56% ee for the (S) -2-chloromandelic acid cyanohydrin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé pour produire des cyanhydrines optiquement actives et les acides alpha -hydroxycarboxyliques correspondants, à partir d'un aldéhyde, d'une source de CN et d'un catalyseur vanadyle-salen optiquement actif dans un système à deux phases liquide-liquide, le mélange réactionnel réagissant à une température comprise entre 0 et 60 DEG C. Selon ce procédé, on utilise 0,8 à 10 équivalents de cyanure et 0,000005 à 0,05 équivalent de catalyseur vanadyle-salen par rapport à l'aldéhyde (concentration 0,5 à 4 mol/l de solvant). Après la réaction, on peut isoler la cyanhydrine optiquement active, ou, après une hydrolyse acide, l'acide alpha -hydroxycarboxylique optiquement actif correspondant, avec de bons excès énantiomériques. Le catalyseur de vanadium utilisé selon l'invention contient un ligand salen, le rapport ligand salen : vanadium (IV) dans le catalyseur étant compris entre 1,4: 1 et 10: 1.
PCT/EP2003/013636 2002-12-18 2003-12-03 Procede pour produire des cyanhydrines optiquement actives et leurs acides mandeliques correspondants Ceased WO2004054966A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2002159164 DE10259164A1 (de) 2002-12-18 2002-12-18 Verfahren zur Herstellung von optisch aktiven Cyanhydrinen und deren korrespondierenden Mandelsäuren
DE10259164.4 2002-12-18

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2914091A1 (de) * 1979-04-07 1980-10-16 Bayer Ag Verfahren zur kontinuierlichen herstellung von benzaldehydcyanhydrinen
US20020052523A1 (en) * 2000-11-01 2002-05-02 Clariant Gmbh Process for preparing optically active cyanohydrins and secondary products
WO2002066410A1 (fr) * 2001-02-16 2002-08-29 Avecia Limited Preparation de derives d'acide mandelique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2914091A1 (de) * 1979-04-07 1980-10-16 Bayer Ag Verfahren zur kontinuierlichen herstellung von benzaldehydcyanhydrinen
US20020052523A1 (en) * 2000-11-01 2002-05-02 Clariant Gmbh Process for preparing optically active cyanohydrins and secondary products
WO2002066410A1 (fr) * 2001-02-16 2002-08-29 Avecia Limited Preparation de derives d'acide mandelique

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Publication number Publication date
DE10259164A1 (de) 2004-07-01

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