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WO2000023608A1 - Preparation d'amino-alcools - Google Patents

Preparation d'amino-alcools Download PDF

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Publication number
WO2000023608A1
WO2000023608A1 PCT/NL1999/000655 NL9900655W WO0023608A1 WO 2000023608 A1 WO2000023608 A1 WO 2000023608A1 NL 9900655 W NL9900655 W NL 9900655W WO 0023608 A1 WO0023608 A1 WO 0023608A1
Authority
WO
WIPO (PCT)
Prior art keywords
species
pseudomonas
hydroxy
compound
candida
Prior art date
Application number
PCT/NL1999/000655
Other languages
English (en)
Inventor
Martin Karutz
Marcel Gerardus Wubbolts
Holger Paschold
Original Assignee
Dsm Biotech Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dsm Biotech Gmbh filed Critical Dsm Biotech Gmbh
Priority to AU63731/99A priority Critical patent/AU6373199A/en
Publication of WO2000023608A1 publication Critical patent/WO2000023608A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions

Definitions

  • the present invention relates to a process - for the preparation of an amino alcohol, in which the corresponding ⁇ -hydroxy keto compound is brought into contact with a dehydrogenase with the aid of a cofactor in the presence of a compound that contains an -NH group .
  • the present invention also relates to the preparation of ⁇ -hydroxy keto compounds from the corresponding amino alcohols with the aid of a dehydrogenase in the presence of a cofactor.
  • the enzymatic reaction is often carried out in practice at a temperature of 10-70°C and preferably 20-40°C.
  • the pH at which the enzymatic reaction is conducted is similarly not critical and preferably lies in the range between 4 and 9.
  • the micro-organism from which the dehydrogenase used in the preparation of amino alcohols is derived can be for example a bacterium, a yeast or a fungus.
  • the micro-organisms in question preferably belong to one of the following genera: Candida, Zygoascus, Pseudomonas, Burkholderia, Comomonas, Vibrio, Enterobacter, Yersinia, Klebsiella, and Citrobacter, and especially: Pseudomonas fluorescens, Pseudomonas luteoia, Pseudomonas putida, Pseudomonas species, Burkholderia cepacia, Comomonas testosteroni , Vibrio fluvialis, Vibrio species, Enterobacter cloacae, Enterobacter agglomerans, Yersinia species, Klebsiella species, Citrobacuer fruend
  • MUCL 41424 it has been found that, in the presence of such a micro-organism, the ⁇ -hydroxy keto compound can readily be prepared in si tu from the corresponding diol and even from the corresponding olefinically unsaturated compound. It has thus been found also possible to prepare amino alcohols from the corresponding olefinically unsaturated compounds in a one-pot process. The invention therefore also relates to such a one-pot process.
  • the enzyme preparation used in the present invention is not restricted by purity and the like, so both a crude enzyme solution and a purified enzyme can be used, and the preparation can also consist of (permeabilized and/or immobilized) cells that possess the required activity or of a homogenate of cells with such an activity.
  • the enzyme can also be used in immobilized form or in chemically modified form. If the enzyme preparation used also contains some undesirable, contrary enzymatic activity, it is recommended that this undesirable activity should be removed or suppressed in order to ensure a maximum selectivity.
  • the invention is not limited in any way by the form in which the enzyme is used for the present invention. It is of course also within the scope of the invention to use a related enzyme that is derived e.g. from a mutant or a genetically modified micro-organism.
  • the micro-organisms can be cultured on various mixtures of compounds that make the growth of the cells possible in the composition used under the conditions described above. According to the procedure adopted, it is possible to use as a carbon source made from carbohydrates (e.g. glucose or sucrose), organic acids (e.g. acetic, lactic or succinic acid) or salts thereof. It is also possible to employ substrates that are converted along the metabolic route and contain the required enzymes.
  • the nitrogen source can be provided by organic nitrogen compounds (e.g. yeast extract, casamino acids and peptone) , inorganic nitrogen compounds (e.g. ammonium sulphate or ammonium phosphate) or amino alcohols that form the product of the reaction involved. If necessary, vitamins and trace amounts of organic or inorganic salts can also be added to the medium.
  • the micro-organisms are often cultured in practice at a temperature of between 20 and 50°C and preferably at 25-30°C.
  • the cultures are often incubated at a pH of 4-9, the preferred pH range being 4.5-5.5 for yeasts and fungi, and 6.5-7.5 for bacteria.
  • the cultures are e.g. aerated by passing through them a gas containing molecular oxygen, or else by introducing into them another gaseous or liquid compound that can be used by the organisms as a source of oxygen. Another alternative is to stir or shake the culture mechanically.
  • the micro-organisms can be cultured in a reaction mixture that contains a single aqueous liquid phase or in a mixture of two liquid phases, one of which is aqueous and the other is an organic solvent such as an alcohol (particularly decanol) , an alkane (e.g. decane) , or a synthetic or natural oil (e.g. silicone oil, rapeseed oil or sunflower- seed oil etc.) .
  • an alcohol particularly decanol
  • an alkane e.g. decane
  • a synthetic or natural oil e.g. silicone oil, rapeseed oil or sunflower- seed oil etc.
  • the micro-organisms can be cultivated in a batch process, a fed-batch process or a continuous culture.
  • all the substrates are introduced into the reaction mixture at the beginning of the reaction.
  • the substrates are partly introduced during the process, and f the reaction mixture comprises two phases, the substrates can also be added as a solution in the organic solvent or in the oil.
  • the intended substrates and the other components of the medium can be added separately in order to decouple the product formation from the residence time.
  • the concentration of both the substrate and the product can be chosen so that both are present in dissolved form in the reaction mixture.
  • concentrations can also be chosen to be so high that part of the substrate and/or of the product is present in solid form.
  • Single-stage processes are characterized by a substrate conversion that is simultaneous with cell growth.
  • the micro-organisms are first cultured, and the resulting biomass or parts of it is brought into contract with the substrate, optionally after the cell residues have been removed.
  • This approach also makes cross-feeding possible, that is to say specific components such as buffer salts are added to further improve the conversion of the substrate in the second stage of the process, as is known to the person skilled in the art.
  • ⁇ -Hydroxy keto compounds can also exist in the tautomeric form, and therefore this form is also included in the term " ⁇ -hydroxy keto compounds".
  • ⁇ -hydroxy keto compounds can be used in the process according to the present invention: ⁇ -hydroxy ketones and ⁇ -hydroxy aldehydes, especially primary and secondary aromatic hydroxy ketones, for instance: 2 -hydroxy- 1-phenylethan- 1 -one , 2 -hydroxy- 1 - phenylpropan-1-one, 2 -hydroxy- 1-phenylbutan-l-one , 2- hydroxy-2 , 3 , 4-trihydronaphthalen-l-one , 3-hydroxy-4- phenylbutan-2-one, 2 -hydroxy-1-phenylpentan-3 -one, 2- hydroxy-l-phenylhexan-3 -one, and 2 -hydroxy-1-indanone primary and secondary aliphatic hydroxy ketones, for instance: 1-hydroxyacetone, 3-hydroxybutan-2-one, 1- hydroxybutan-2-one, 2-hydroxypentan-3-one, 1- hydroxypentan-2-one, 2-hydroxyhexan-3 -one, 3- hydroxypent-4-
  • ⁇ -hydroxy keto compounds that can be used in the process according to the present inventions are in some cases commercially available and can be prepared by a conventional method, e.g. chemically as described by Baskaran et al . (1986) in J.O.C. 54, 5182 and by N.S. Srinivasan and D.G. Lee (1979) in Synthesis (7), 520-1, or enzymatically as described by S. Ui et al . (1996) in J. Ferment. Bioeng., 81 (5), 386-389.
  • the ⁇ -hydroxy keto compounds can also be prepared in si tu from the corresponding diol, as described above.
  • the diols are in some cases commercially available or can be prepared conventionally as described by J.M. Brand et al . (1992) in Appl . Environ. Microbiol . , 58 (10), 3407-9 and by T. Hudlicky et al . (1996) in J. Am. Chem. Soc . , 118 (44), 10752-65.
  • the diols can also be prepared in si tu , as described above, from the corresponding olefinically unsaturated compound which as a rule is available commercially per se .
  • Any compound acting as a donor of a primary or secondary amino group can be used as the amino donor, for example ammonia, inorganic ammonium compounds (e.g. ammonium salts, and especially ammonium sulphate or ammonium phosphate) or, preferably in the case of whole cells, an (organic) compound containing a primary or secondary amino group, for instance glutamine .
  • the cofactor can be a hydrogen-transferring cofactor, for example NADH, NADPH or FADH 2 .
  • the cofactor is preferably regenerated, e.g. by the conventional methods, especially enzymatically, for example with the aid of formate dehydrogenase or alcohol dehydrogenase, or else by an electrochemical method.
  • the invention is further explained below with reference to the following examples but is not limited by them.
  • Natural samples of sewage, sewage sludge and soil were used as the starting material in the selection of a biocatalyst capable of converting 1- keto-2-hydroxyindane (chosen as an example of an ⁇ - hydroxy keto compound) into l-amino-2-hydroxyindane, representing an example of an amino alcohol. These samples were incubated in a complex medium and in a mineral medium.
  • the complex medium consisted of: 10 g/1 yeast extract, 10 g/1 peptone and 5.0 g/1 sodium chloride.
  • the mineral medium contained the following constituents: 2.6 g/1 trisodium citrate dihydrate, 1 g/1 magnesium sulphate heptahydrate , 0.5 g/1 sodium chloride, 0.08 g/1 ferrous sulphate heptahydrate, 0.1 g/1 calcium chloride dihydrate, and 5.5 g/1 phosphoric acid.
  • a stock solution (1 ml/1) was added containing the following further minerals: 2.0 g/1 aluminium sulphate.18 H 2 0, 0.7 g/1 cobalt (II) sulphate hexahydrate, 2.5 g/1 copper (II) sulphate pentahydrate, 0.5 g/1 boric acid, 20.0 g/1 manganese (II ) chloride tetrahydrate, 3.0 g/1 Na 2 Mo0 4 .2H 2 0, 2.0 g/1 NiS0 4 .3H 2 0, and 15.0 g/1 ZnS0 4 .7H 2 0.
  • the pH was adjusted to 5 by adding KOH, and the medium was treated m an autoclave for 15 min at 121°C.
  • a solution of 0.01 g/1 thiamme hydrochloride and 0.001 g/1 biotin was added to the sterile medium after passing the latter through a microfilter.
  • 2 g/1 of a racemic mixture of (IS, 2R) -cis-l-amino-2-indanol and (1R, 2S) -cis-l-amino-2 -indanol were added as the sole nitrogen source before sterilizing the medium.
  • 4 g/1 glucose were introduced in the form of a sterile solution as the carbon source.
  • a mineral medium without sodium citrate was also used, which - unlike the medium described above - was titrated to pH 7 with potassium hydroxide. The cuituring was done at 28 and 37°C. Organisms that could grow on the mineral medium by utilizing l-amino-2 -indanol were streaked out and kept on an agar plate prepared with a mineral medium and agar (15 g/1) .
  • An example of an organism capable of growing on l-amino-2 -indanol was the isolate Candida sp. MUCL 41424, which had been isolated from a Canadian soil sample contaminated with bitumen.
  • Example 2 The isolate Candida s . MUCL 41424 was cultured on the mineral medium at pH 5 with 3 g/1 1- amino-2 -indanol as the nitrogen source. 10 ml of the medium were introduced in a 100-ml shaker flask, which was placed on a shaker and incubated at 25 °C. The extent of cell growth was determined by measuring the optical density of the medium with a spectrophotometer at 620 nm. High-performance liquid chromatography (HPLC) was used to determine the concentration of the l-amino-2 -indanol (c) under the following chromatographic conditions: column: Nucleosil 120-5 C 18 ,
  • the culture reached an optical density of 10 after incubation for 110 h. This indicated that the cells could utilize l-amino-2 -indanol as a nitrogen source and convert it into l-keto-2-hydroxyindane (see Fig. 1, wherein c is given as a function of time (in hours) ) .
  • the isolate Candida sp . MUCL 41424 was cultured on a complex medium containing 11.7 g/1 Difco Yeast Carbon Base (YCB) and 6.7 g/1 Difco Yeast Nitrogen Base (YNB) .
  • the cells were harvested at an optical density of 18 (measured at 620 nm) by centrifuging the medium at 6000 rpm for 5 min.
  • the cells were diluted with potassium phosphate buffer (pH 7.2) to an optical density of 220.
  • 0.6 ml of diluted cells were then mixed with 1.2 g of 0.5 -mm glass beads and shaken for 12 min in a Retsch type laboratory glass-bead mill. The beads were then removed by sedimentation in a bench centrifuge.
  • Example 4 The following substances were used as the ⁇ -hydroxy keto compound instead of l-keto-2- hydroxyindane in an experiment comparable with Example 3: hydroxyacetone ( ⁇ ) , 2 -hydroxy- 1-indanone (•) and 3- hydroxy-2-butanone ( ⁇ ) (and control reaction (o) ) .
  • Fig. 3 shows the decrease in the NADH concentration, determined with a spectro photometer at 340 nm as a function of time (t) in minutes. These results indicate that all the components were converted by the enzyme, causing a decrease in the NADH concentration. Concommittent formation of amino groups by the enzyme has been observed by HPLC analysis of the assay incubation mixture (precolumn derivatization carried out as in example 2) .
  • Example 5 Example 3 was repeated on a larger scale to make it possible to determine the formation of 1-amino- 2 -indanol directly. For this purpose, the reaction was carried out at 25°C in a mixture containing 10 ml of potassium phosphate buffer (pH 7.2), 100 ⁇ l of NADH
  • reaction was initiated by the addition of 1 ml of 3 g/1 of l-keto-2-hydroxyindane, and it was stopped after 3 h of reaction time by the addition of
  • the isolate Candida sp . MUCL 41424 was incubated in a 1 -litre shaker flask containing 100 ml of the Yeast Nitrogen Base medium and 0.1 ml of indene, with mechanical stirring. After this first stage, the following two substances were added to the culture at set times every day for 14 days: 1C ml of Yeast Nitrogen Base (67 g/1) and 1-2 ml cf a l:5-mixture (by volume) of indene and silicone oil.
  • the results shown in Fig. 4 indicate that the isolate Candida sp . MUCL 41424 can convert indene into (IS , 2R) -cis-l-amino-2-indanol with a high stereospecificity and a high enantioselectivity.
  • the upper part represents the reference material racemic cis-l-amino-2-indanol and racemic trans-1- amino-2- indanol ; the lower part represents the sample.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Procédé permettant de préparer un amino-alcool, qui consiste à mettre en contact un composé α-hydroxy-céto avec une déshydrogénase, avec l'aide d'un cofacteur, en présence d'un composé contenant un groupe NH. Le composé hydroxy-céto est de préférence converti en présence d'un micro-organisme, ou de parties dudit micro-organisme, appartenant notamment aux genres suivants: Candida, Zygoascus, Pseudomonas, Burkholderia, Comomonas, Vibrio, Enterobacter, Yersinia, Klebsiella et Citrobacter, notamment: Pseudomonas fluorescens, Pseudomonas luteola, Pseudomonas putida, Pseudomonas species, Burkholderia cepacia, Comomonas testosteroni, Vibrio fluvialis, Vibrio species, Enterobacter cloacae, Enterobacter agglomerans, Yersinia species, Klebsiella species, Citrobacter fruendii, Zygoascus hellenicus, Candida species, avec une préférence particulière pour Candida sp. MUCL 41421 et plus particulièrement pour un micro-organisme dérivant de Candida sp. MUCL 41424. Le composé hydroxy-céto est de préférence préparé à partir du composé oléfiniquement insaturé correspondant et le cofacteur est régénéré.
PCT/NL1999/000655 1998-10-20 1999-10-20 Preparation d'amino-alcools WO2000023608A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63731/99A AU6373199A (en) 1998-10-20 1999-10-20 Preparation of amino alcohols

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL1010354A NL1010354C2 (nl) 1998-10-20 1998-10-20 Bereiding van aminoalcoholen.
NL1010354 1998-10-20

Publications (1)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1020515A2 (fr) * 1999-01-18 2000-07-19 DAICEL CHEMICAL INDUSTRIES, Ltd. Amino-alcool déshydrogénase et son préparation et utilisation
DE102009000592A1 (de) 2009-02-04 2010-08-05 Evonik Degussa Gmbh Verfahren zur Herstellung von Aminogruppen tragenden, multizyklischen Ringsystemen

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000966A1 (fr) * 1995-06-20 1997-01-09 Merck & Co., Inc. Conversion d'indene en (1s)-amino-(2r)-indanol depourvu de tout stereo-isomere, par combinaison de bioconversion de dioxygenase et d'etapes chimiques
WO1997025436A1 (fr) * 1996-01-12 1997-07-17 Nippon Steel Chemical Co., Ltd. Procede de production de derives de l'indane
WO1998006866A1 (fr) * 1996-08-14 1998-02-19 Merck & Co., Inc. Conversion d'indene en (1s)-amino-(2r)-indanol depourvu de tout stereo-isomere, par combinaison de bioconversion de dioxygenase et d'etapes chimiques
NL1005832C2 (nl) * 1997-04-17 1998-10-20 Dsm Nv Werkwijze voor de bereiding van CIS-(1S,2R)-aminoindanol.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000966A1 (fr) * 1995-06-20 1997-01-09 Merck & Co., Inc. Conversion d'indene en (1s)-amino-(2r)-indanol depourvu de tout stereo-isomere, par combinaison de bioconversion de dioxygenase et d'etapes chimiques
WO1997025436A1 (fr) * 1996-01-12 1997-07-17 Nippon Steel Chemical Co., Ltd. Procede de production de derives de l'indane
WO1998006866A1 (fr) * 1996-08-14 1998-02-19 Merck & Co., Inc. Conversion d'indene en (1s)-amino-(2r)-indanol depourvu de tout stereo-isomere, par combinaison de bioconversion de dioxygenase et d'etapes chimiques
NL1005832C2 (nl) * 1997-04-17 1998-10-20 Dsm Nv Werkwijze voor de bereiding van CIS-(1S,2R)-aminoindanol.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAJIRO H ET AL: "Enantioselective synthesis of 2-hydroxy-1-indanone, a key precursor of enantiomerically pure 1-amino-2-indanol", TETRAHEDRON: ASYMMETRY, vol. 9, no. 6, 27 March 1998 (1998-03-27), pages 907-910, XP004112139 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1020515A2 (fr) * 1999-01-18 2000-07-19 DAICEL CHEMICAL INDUSTRIES, Ltd. Amino-alcool déshydrogénase et son préparation et utilisation
EP1020515A3 (fr) * 1999-01-18 2002-08-07 DAICEL CHEMICAL INDUSTRIES, Ltd. Amino-alcool déshydrogénase et son préparation et utilisation
DE102009000592A1 (de) 2009-02-04 2010-08-05 Evonik Degussa Gmbh Verfahren zur Herstellung von Aminogruppen tragenden, multizyklischen Ringsystemen
WO2010089171A2 (fr) 2009-02-04 2010-08-12 Evonik Degussa Gmbh Procédé de préparation de systèmes multicycliques portant des groupes amino

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NL1010354C2 (nl) 2000-04-25
AU6373199A (en) 2000-05-08

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