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  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J2219/00277—Apparatus
  • B01J2219/00479—Means for mixing reactants or products in the reaction vessels
  • B01J2219/00488—Means for mixing reactants or products in the reaction vessels by rotation of the reaction vessels
  • B01J2219/0049—Means for mixing reactants or products in the reaction vessels by rotation of the reaction vessels by centrifugation
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  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J2219/00497—Features relating to the solid phase supports
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  • B01J2219/00536—Sheets in the shape of disks
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• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00603—Making arrays on substantially continuous surfaces
  • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
  • B01J2219/0061—The surface being organic
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01J2219/00603—Making arrays on substantially continuous surfaces
  • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
  • B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
• • 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
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  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00603—Making arrays on substantially continuous surfaces
  • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
  • B01J2219/00623—Immobilisation or binding
  • B01J2219/00626—Covalent
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00603—Making arrays on substantially continuous surfaces
  • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
  • B01J2219/00632—Introduction of reactive groups to the surface
  • B01J2219/00635—Introduction of reactive groups to the surface by reactive plasma treatment
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01J2219/00603—Making arrays on substantially continuous surfaces
  • B01J2219/00659—Two-dimensional arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
  • B01J2219/00722—Nucleotides
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
  • B01J2219/00725—Peptides
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J2219/00729—Peptide nucleic acids [PNA]
• • B—PERFORMING OPERATIONS; TRANSPORTING
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  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
  • B01J2219/00731—Saccharides
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B40/00—Libraries per se, e.g. arrays, mixtures
  • C40B40/04—Libraries containing only organic compounds
  • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B40/00—Libraries per se, e.g. arrays, mixtures
  • C40B40/04—Libraries containing only organic compounds
  • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B40/00—Libraries per se, e.g. arrays, mixtures
  • C40B40/04—Libraries containing only organic compounds
  • C40B40/12—Libraries containing saccharides or polysaccharides, or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
  • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

• HTS High Throughput Screening
• Positions in the array are defined and the interaction tests can be carried out with fast pipetting robots.
• the arrays can be generated, for example, by distributing the solutions of prefabricated structures or by serially distributing the solutions of building blocks for their in situ synthesis. Since the efficiency of the method increases proportionally with the number of structures that can be tested simultaneously, measures for the faster production and testing of such arrays in the most miniaturized form possible are desirable.
• Devices and / or methods for producing such repertoires are known and described, in which their elements are either generated in predetermined arrays from reaction vessels (microtider plates, nanotiter plates and similar rectangular arrangements) or in spots (spots, dots) in freely formable arrays the specially activated surface of a suitable carrier material (paper, glass, quartz glass, plastic film, ceramic, film etc.) can be synthesized.
• the elements of the repertoire are generated by a defined chemical chaining of a certain number of reaction partners, which are selected in a defined order from a predetermined pool of substances.
• the reaction partners are loaded serially and the reaction vessels are started up one after the other in a start-stop operation. Required intermediate steps such as a reaction stop, washing out excess reagents etc. are carried out separately, in some cases also outside of the apparatus.
• the object of the invention is to design a device according to the generic term such that it allows a comparatively large number of elements of an array to be operated quickly and with high precision.
• the substrate has the shape of a rotating body rotating continuously or at least quasi-continuously, in small steps, about its axis and the dosing head moves in a single coordinate, constant accelerations and decelerations are at least largely eliminated.
• the elements in the form of spots can appear extremely close together and in a correspondingly large number.
• a further acceleration is achieved by using a large number of dosing heads, which can also be moved continuously with correspondingly short delivery intervals.
• the dosing processes are coordinated with the rotation movement in such a way that the correct component is dosed onto every position in the array.
• Each individual structure in the array is produced step by step by chemical anchoring of one to one hundred, preferably up to 20, building blocks on a flat, unstructured substrate. Conventional methods of solid phase immobilization and synthesis are used for this. See, for example:
• peptides are built from amino acid building blocks, oligonucleotides from nucleotide building blocks, peptoids from N-substituted glycine building blocks, PNA from N-aminoethyl, N- (purine / pyridine) acetyl-glycine building blocks, oligosaccharides from sugar building blocks, etc.
• PNA N-aminoethyl
• N- (purine / pyridine) acetyl-glycine building blocks oligosaccharides from sugar building blocks, etc.
• Enzymatically catalyzed reactions can also be used for the anchoring reactions.
• the individual structure grows or changes as a result of the sequence of the building blocks in the anchoring reactions. This can be clearly described in the form of a sequence of characters (letters, numbers) for each module. All individual structures are built in parallel, i.e. until they are completed, they all grow by one component per distribution cycle. In addition to the block sequence, the position of the respective element in the array is specified and recorded in a protocol.
• FIG. 1 is a perspective diagram of the device according to the invention in a first embodiment, with a circular cylindrical substrate,
• FIG. 2 shows a perspective diagram of the device according to the invention in a second embodiment, with a disk-shaped substrate
• Fig. 3 is a perspective diagram of the device according to the invention with a disc-shaped substrate in a modified embodiment
• Fig. 4 is a plan view of a disc-shaped substrate of the device according to the invention in a practical embodiment.
• the device according to the invention shown in FIG. 1 has a drum 4 which can be driven to rotate about its axis of symmetry 2 as the axis of rotation and onto which a film-shaped substrate 6 is stretched in a circular cylindrical shape.
• the substrate 6 carries a large number of individual elements 8 made of ligand and acceptor structures in the form of spots, which are arranged at regular intervals in the circumferential direction of the drum 4 as the first coordinate 10 and parallel to the axis of rotation 2 as the second coordinate 12. While only a few elements 8 are shown on the substrate 6 for demonstration purposes, in practice their number can be significantly larger and up to about 160,000, which corresponds to an occupancy density of about 3000 per cm 2 .
• a number of dosing heads 14 in a mutually fixed arrangement carrying dosing head holder 16 arranged in such a way that the mouths 18 of the dosing heads 14 face the surface of the substrate 6 at a short distance.
• the dosing heads 14 are connected via flexible lines, such as 20, to separate storage containers (not shown) for the substances to be metered in, which can be cooled if desired.
• the dosing heads themselves can be designed in the manner of an inkjet printer nozzle or a piezoelectric printer gland.
• the number of dosing heads 14 in the dosing head holder 16 can be between 1 and about 100, preferably up to about 50.
• the dosing heads in this example can, as shown, be arranged in multiple cells.
• the dosing head holder 16 can be moved in the direction of the axis of rotation 2 and thus the second coordinate 12.
• the relevant movement can be controlled as a function of the rotational speed of the drum 4, as can the activity of the dosing heads 14 as a function of the rotational movement of the drum 4 as well as the movement of the dosing head holder 16 can be controlled in order to precisely match the substance in each case to the individual Apply elements 8 of the substrate 6.
• the movement of the dosing head holder 16 can be carried out uniformly continuously or in small steps according to the spacing of the elements 8 in the direction of the second coordinate 12 or a multiple thereof corresponding to the number of dosing heads 14 in the direction of the second coordinate 12 within the dosing head 16.
• the one-dimensional movement of the dosing head holder in connection with the continuous rotary movement of the substrate enables a much faster sequence of the individual dosing processes than is the case with the pipetting machines according to the prior art.
• the substrate 30 has the shape of a circular disk which can be driven to rotate about an axis of rotation 32.
• the disk-shaped substrate 30 carries the individual elements 34, in rings and at the same time radial rows, which run along a first coordinate, 36, or second coordinate, 38, are to be assumed to run continuously.
• a dosing head holder 40 with a row of dosing heads 42 fixedly arranged therein is arranged to be movable radially to the axis of rotation 32.
• the rotary movement of the substrate and the movement of the dosing head holder can then be carried out uniformly or in steps corresponding to the spacing of the individual elements 34 on the substrate, the substances added in each case being held in connection with the positions of the individual elements 34.
• FIG. 3 shows an embodiment similar to that of FIG. 2 in that the substrate 50 in question is again a disk that can be driven to rotate about an axis of rotation 52.
• the elements 54 apart from being ring-shaped along a first coordinate 56, are arranged on arcs along a second coordinate 58, which moves along the dosing head holder 60 when the substrate 50 is in a corresponding position.
• the dosing head holder 60 can be pivoted about a pivot axis 62 arranged outside the substrate 50 in the manner of the pickup head of a turntable.
• the movement of the dosing head for a substrate according to FIG. 3 could also take place along a closed circle.
• FIG. 4 shows a top view of a practical embodiment of a substrate in the manner of the substrate 50 from FIG. 3, in which, however, the number of elements is substantially larger at approximately 10,000. Nevertheless, such a substrate can have the shape and dimensions of a so-called compact disk (CD).
• CD compact disk
• such - or even larger - number of elements on the part of the dosing heads of the device according to the invention can be combined under a single and also uninterrupted rotation of the substrate are operated, with all the relevant operating measures or the resulting structures of the elements being automatically recorded in a protocol.
• the respective substrate 6, 30, 50 etc. In order to have a reference point for the respective location determination of the individual elements 8, 34, 54, the respective substrate 6, 30, 50 etc., as shown, carries an automatically scannable zero marking 70 outside the arrangement of the elements.
• the substrate can be in an enveloping vessel (not shown), which if desired can be flooded with an inert gas. If the dosing head holder is not arranged inside the vessel, the mouths of the dosing heads or even only the substances to be applied therewith can pass through a gap in the vessel.
• all positions of the array are operated according to the specification without or at least practically without start and brake acceleration processes and their time requirement.
• various necessary intermediate steps can be carried out in the same device - and thus without subsequent repositioning with the inherent positioning errors - which consist in treatment that is the same for all elements of the array, for example in the application of certain reagents to the entire sub- strat surface, a rinsing or drying process.
• the substrate or array has between 2500 and 160000 elements, which corresponds to an occupancy density of up to 3000 positions (spots) per cm 2 .
• the volume to be metered in in each case can be 100 pl to 100 nl, the metering frequency 10 to 1000 Hz, preferably approximately 100 Hz.
• the dosing heads can be operated on the principle of Inkjet printer nozzles or be designed to work piezoelectrically.
• the entire substrate can be washed and dried in situ, for example by means of a sponge roller or by accelerated rotation of the substrate in a spin cycle. Forced evaporation or displacement in the gas flow can also be considered.
• the substrate 6 is preferably a flexible but dimensionally stable plastic film, functionalized in the desired manner, which is clamped onto a cylinder wall of the drum 4. After the array has been produced, this film can be removed again and fed to an external interaction test in flat form.
• reagents and solvents for required intermediate steps are either applied to the substrate surface by means of separate nozzles and distributed evenly, or the substrate surface is immersed by immersing the Substrate, if necessary with a slow rotation in a tub filled with these reagents or solvents completely.
• a substance or rinsing liquid can also be applied to the entire substrate surface in that it is applied to the central region of the substrate with increased rotational speed, in order to move away from there by the centrifugal force over the Spread the substrate surface outwards.
• the underside of the substrate can be used, for example optically readable, to record information.
• information such as the item positions and the type of _
• the dosing heads combined in the respective dosing head holder are guided stepwise or continuously along the second coordinate over the substrate surface.
• the metering heads relative to the substrate sequentially, the positions ⁇ Xi, X (i + i) S ' ⁇ (i + 2) S' ⁇ (i + 3) s, ..., ⁇ (i + n) s a
• i is the respective positioning step
• n is the number of dosing heads in the dosing head holder 16
• S is the distance between the dosing heads in the direction of the second coordinate. It does not matter whether the positioning steps according to FIGS. 1 and 2 take place in a straight line or according to FIG. 3 as curved or angular movements.
• the dosing heads take the positions Y m ⁇ , Y m2 , at any time along the first coordinate with respect to the substrate mt.
• the coordinates Xi; Y m span the entire array of the repertoire to be created and clearly indicate the positions of the individual elements (spots). With these positions, the respective substantial properties for each element can be saved in the repertoire (library).
• the substrate can be made of glass, ceramic or polyolefins, with or without fillers such as polypropylene (PP), polyethylene (PE), polymethylpentene (PMP), polychlorotrifluoroethylene (PCTFE), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), ethylene vinyl acetate Copolymer (EVA) or ethylene-vinyl alcohol copolymer (EVAL) and are in the form of a fo lie, membrane or plate can be designed. It is either functionalized as described below under A) and B) in a two-stage process on the surface, or amino groups are introduced directly, as described under C) or D).
• the graft polymerizations described under E) enable the functionalization of polymer surfaces by using heteroatom-substituted monomers by multiplying the number of originally introduced functionalities while simultaneously forming larger distances from the substrate surface (spacer).
• functional groups preferably hydroxyl groups
• the undesired functionalities additionally generated in the first step such as carboxylic acids and their esters, aldehydes, ketones and alkenes, are converted into hydroxyl groups.
• the surface concentration of functional groups can be controlled via the reaction time and temperature during the first reaction step.
• the substrates functionalized in this way are used directly for the synthesis or previously provided with spacers and / or linkers.
• Oxygen flow 20-40 1 / h
• Dehydrofluorination with sodium hydroxide under phase transfer conditions is carried out analogously to a procedure described in A.J. Dias, T.J. McCarthy, Macromolecules 1984, 17, 2529-2531.
• Dehydrofluorination with DBU is carried out analogously to a procedure described in J.V. Brennan, T.J. McCarthy, Polym. Prepr. (Am. Chem. Soc) Div. Polym. Chem. 1989, 30, 152-153.
• naphthalene sodium solution is prepared according to H.F. Ebel and A. Lüttringhaus in Houben-Weyl, Methods of Organic Chemistry, Volume XIII / 1, Georg Thieme Verlag Stuttgart 1970, p. 381.
• the substrate is covered with a protective gas during the specified reaction time with a 0.1 M -1.25M solution of naphthalene sodium in THF and shaken. Then the substrate is washed with water, 1M aqueous sodium hydroxide solution, 1 M aqueous hydrochloric acid and tetrahydrofuran and then dried. 6. Reaction: Reduction of PTFE and PCTFE with benzoin
• hydroboration with borane / dimethyl sulfide complex and oxidation with hydrogen peroxide or sodium perborate is carried out according to the rules described in CF Lane, HL Myatt, J. Daniels, HB Hopps, J. Org. Chem. 1974, 39, pp. 1437-1438 and S. 3052-3054, GW Kabalka, TM Shoup, NM Goudgaon, J. Org. Chem. 1989, 54, 5930-5933.
• the polypropylene samples were 115 mm in diameter and 1.9 mm in thickness. In addition to the entire samples, quartered sample pieces were also used to determine the area coverage with amino groups. In addition to the PP samples, glass substrates and double-sided polished Si samples were also coated in the plasma polymer coatings. The samples were subjected to the following cleaning steps before plasma treatment or coating:
• the polypropylene samples were removed from the drying cabinet immediately before loading the plasma system and placed on the lower electrode. Before a pretreatment or coating test, the system was evacuated for at least 1 hour in order to obtain the best possible final vacuum and thus low residual gas contamination. In this time it will be have brought the sample temperature close to the ambient temperature.
• the sample temperature increases only slightly during a surface treatment.
• the deposition of plasma polymer layers in a low pressure reactor is a suitable method for coating plastic surfaces.
• the properties of the deposited layers can be specifically influenced in this process by the choice of the monomers used.
• the monomers are passed into the process in gaseous form and excited by a plasma to polymerize on the substrate surface. In this way, through the crosslinking of the monomers, a plasma polymer layer grows up. Only a low energy density is required to excite plasma polymerization. If the plasma power is too high, on the other hand, there is an increasing decomposition and cleavage of the monomer molecules.
• a plasma pretreatment was carried out before the coating process. This process step was carried out with an argon / oxygen mixture with higher plasma power in order to additionally clean and activate the sample surfaces.
• the plasma polymer coatings were carried out with allylamine in an argon plasma.
• the surface concentration of amino groups can be significantly increased after plasma polymerization with allylamine by treatment for two hours with 50% trifluoroacetic acid in dichloromethane at room temperature.
• T he described methods can also be applied to glass and metal oxide ceramics.
• the array of target structures is determined using software and transformed into a chronological sequence of metering operations for the building blocks, reagents and solvents that are required for the chemical / enzymatic construction of the compound library. All movements and switching of valves are controlled by a computer.
• Variant 1 library of immobilized structures
• the substrate surface covered with the library of compounds is brought into contact with the solution of a binding partner (ligand or acceptor) and incubated.
• a binding partner ligand or acceptor
• the binding partner is detected by determining the change in fluorescence intensity after interaction between the labeled library element and the binding partner.
• the structure of the library element can be marked with anthranilic acid (2-aminobenzoic acid) and the binding of, for example, a protein can be demonstrated by energy transfer from the anthranilic acid residue to a tryptophan residue in the protein.
• Variant 2 library with soluble structures
• the functionalized substrate surface is first derivatized with a "linker".
• the library is then built on the linker functions.
• the linker allows the covalent chemical linkage with the substrate surface to be cleaved after the library has been synthesized.
• the library elements, which are then still locally separated, are taken up by subsequent distribution of small drops of a suitable solvent and from there individually transferred into a test arrangement.
• the cleavage reagent is distributed in the form of small drops to the locations of the library elements, whereupon the cleaved compounds are individually transferred to a test arrangement.
• Reaction temperature room temperature, i.e. approx. 21 ° C
• the substrate is covered with a 0.5 M solution of chromium trioxide in the specified solvent and shaken at the specified reaction temperature. After the reaction time, the substrate is washed with water, 0. IM aqueous EDTA solution and ethanol and then dried.
• Reaction temperature room temperature, i.e. about 21 ⁇ C
• the substrate is washed in a container with the ozone generated by an ozone generator in an oxygen stream during the specified reaction time.
• the ozone generator came from the company Fischer Labor-und Maschinenfabric, Bonn - Bad Godesberg
• the substrate is covered with a solution of 30% aqueous hydrogen peroxide solution in trifluoroacetic acid in a volume ratio of 1: 9 and heated to the specified reaction temperature. Then the substrate is washed with water, methanol and dichloromethane and then dried.
• the substrate is covered with an IM solution of DBU in the specified solvent and shaken during the specified reaction time. Then the substrate is washed with water, methanol and dichloromethane and then dried.
• Reaction temperature room temperature, i.e. about 21 ⁇ C to 80 ⁇ C
• the substrate is washed with an 8M aqueous solution of sodium hydroxide and a phase transfer catalyst, e.g. Tetra-n-butylammonium bromide (10 mg to 15 ml), covered and shaken. Then the substrate is washed with water, methanol and dichloromethane and then dried.
• a phase transfer catalyst e.g. Tetra-n-butylammonium bromide (10 mg to 15 ml)
• Reaction temperature room temperature, i.e. approx. 21 ° C
• the substrate is covered with a protective gas during the indicated reaction time with a 0. IM - 1.25M solution of naphthalene sodium in THF and shaken. Then the substrate is washed with water, 1M aqueous sodium hydroxide solution, 1M aqueous hydrochloric acid and tetrahydrofuran and then dried.
• a 0.4 M solution of benzoin in DMSO is prepared under protective gas and moisture exclusion, whereupon this solution is added dropwise to a 0.4 M solution of potassium tert. -butylate in DMSO, which covers the substrate.
• the mixture is then shaken at the specified temperature for the specified reaction time. Then the substrate is washed with water, methanol and dichloromethane and then dried.
• the substrate is refluxed in a 2M solution of sodium hydroxide in methanol for the indicated reaction time. Then the substrate is washed with 1M aqueous hydrochloric acid, water, methanol and dichloromethane and then dried.
• Reaction temperature room temperature, i.e. about 21 ⁇ c, to 50 ⁇ c
• Solvents anhydrous inert solvents such as Tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dioxane, benzene, toluene, alkanes (C5-C8)
• the substrate is covered with a 0.1 ⁇ m solution of borane-THF complex or borane-dimethyl sulfide complex in the specified solvent during the specified reaction time and shaken at the specified reaction temperature.
• the substrate is covered with a solution of 30% aqueous hydrogen peroxide and 1.5 M aqueous sodium hydroxide solution in a volume ratio of 1: 2 and shaken at room temperature for 1-3 hours. Then the substrate is washed with 1M aqueous sodium hydroxide solution, 1M aqueous hydrochloric acid, water, DMF and dichloromethane and then dried.
• Reaction temperature room temperature, ie approx. 21 ° C to 50 ° C
• the substrate is covered with sodium perborate and the specified solvent and shaken for 1-3 hours at the specified reaction temperature. Then the substrate is washed with 1M aqueous sodium hydroxide solution, 1M aqueous hydrochloric acid, water, DMF and dichloromethane and then dried.

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• 1998
  • 1998-04-28 DE DE19818999A patent/DE19818999A1/de not_active Withdrawn
• 1999
  • 1999-04-26 EP EP99924825A patent/EP1089812B1/de not_active Expired - Lifetime
  • 1999-04-26 AT AT99924825T patent/ATE234675T1/de not_active IP Right Cessation
  • 1999-04-26 WO PCT/EP1999/002811 patent/WO1999055455A2/de active IP Right Grant
  • 1999-04-26 DE DE59904641T patent/DE59904641D1/de not_active Expired - Lifetime
  • 1999-04-26 DK DK99924825T patent/DK1089812T3/da active
  • 1999-04-26 AU AU41357/99A patent/AU4135799A/en not_active Abandoned
  • 1999-04-26 ES ES99924825T patent/ES2195575T3/es not_active Expired - Lifetime

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