WO2001096262A1

WO2001096262A1 - Method for producing dendritic structures

Info

Publication number: WO2001096262A1
Application number: PCT/DE2001/002230
Authority: WO
Inventors: Manfred Wiessler; Stefan Raddatz
Original assignee: Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
Priority date: 2000-06-16
Filing date: 2001-06-13
Publication date: 2001-12-20
Also published as: DE10029709A1

Abstract

The invention relates to a method wherein high-substituted alkynyl halogenides are reacted with CH-acid carbonyl compounds in the presence of a reducing agent.

Description

Process for the production of dendritic structures

The invention relates to a method for producing dendritic structures.

Dendritic structures, especially dendritic saccharide structures, have become increasingly important for biological applications in recent years. It has been recognized that dentritic structures play a role in biological recognition processes, e.g. in the case of metastasis or infection by viruses or bacteria (Varki, Glycobiology 1993, 3, 97). However, the reactions used to build up these structures all suffer from the disadvantage that they offer no possibility of introducing a wide variety of (sugar) structures in a few reaction steps.

The present invention is therefore based on the object of providing a method with which dendritic structures (in particular dendritic saccharide structures with high variability) can be produced simply, inexpensively, with high variability and in good yields.

According to the invention, this is achieved by the subject matter in the claims.

The present application thus relates to a process in which highly substituted alkynyl halides are reacted with CH-acidic carbonyl compounds in the presence of a strong base.

Dendrimers / dendritic structures are three-dimensional, highly ordered oligomeric or polymeric compounds. These have several reactive groups. Substances are bound to these groups. In this way, first generation dendrimers are obtained. To the substances of the First generation dendrimers can be bound to other substances which can then be linked to other substances. Second generation dendrimers are obtained. By repeating this sequence of reactions, higher generation dendrimers are obtained.

The present invention is based on the finding that even highly substituted alkynyl halides can alkylate reactive CH-acidic compounds repeatedly (e.g. up to four times) in good to very good yields. Any ester groups or protective groups which may be present can then be split off and the remaining keto function reduced, so that an alcohol function is formed. This alcohol function can be alkylated again with a reactive alkynyl halide, which means the generation of a spacer in the resulting dendrimeric structure. Therefore, preferred spacers are saturated or unsaturated hydrocarbon chains, preferably C ₂ -C ₁₈ groups, which may contain heteroatoms, such as oxygen, sulfur or nitrogen atoms.

The underlying reaction scheme is shown in Fig. 1. A preferred reaction scheme for the production of dendrimeric saccharide structures is shown in FIG. 2.

According to the invention, any of a C-H-acidic carbonyl compound

Hydrocarbon are to be understood with a -C = O grouping, in which the removal of one or more protons is facilitated. Preferred C-H-acidic compounds are diethyl acetone dicarboxylate, acetoacetic ester, diethyl malonate, di (2-trimethylsilylethyl) acetone dicarboxylate, di-t-butyl acetone dicarboxylate.

According to the invention, an alkynyl halide is understood to mean all aliphatic, alicyclic or aromatic hydrocarbons which have an at least bisubstituted CC triple bond and have a halogen substituent. The halogen substituent can be fluoride, bromide, chloride or iodide, with bromide being preferred. Very preferred compounds are 2-alkynyl halides, such as 1-bromo-2-butyn-4-ol or 1-bromo-2-hexin-6-ol. The alkynyl halides preferably have one on at least one of their ends -14/6

3

Modification R on. The alkynyl halides therefore preferably have the following structure: Hal-CH ₂ -C≡CR [with R = chemical protective groups (for example acyl groups (for example benzoyl), alkyl groups (for example methyl, ethyl, n-propyl, isopropyl), tert- Butyl groups, benzyl groups, silyl groups), pharmaceutical active ingredients, such as peptides or glycopeptides, R = saccharide is preferred]. The term "saccharide" encompasses saccharides of all kinds, in particular monosaccharides in all stereoisomeric and enantiomeric forms, for example pentoses and hexoses, such as α- and β-D-glucose and derivatives thereof, such as with protecting groups, for example benzyl-protected saccharides and / or with functional groups Groups such as amino groups, phosphate groups or halide groups, modified saccharides. Saccharides here are especially inositols, very particularly optically active derivatives of myo-inositol and quebrachitol, for example from galactinols, both from plant sources, such as sugar beets, and from milk products, or derivatives obtained by enzymatic separation of enantiomers. The saccharides can be the same or different from one another. Between the actual alkyl halide and the

In order to reduce steric interactions, linkages or spacers, such as (CH ₂ ) _n groups with n = 1-20, can also be present, whereby these can also contain heteroatoms, such as N, O and S.

In a preferred embodiment of a dendrimeric structure produced according to the invention, a spacer as defined above is present between the core structure originating from the C-H-acidic compound and one or at most all of the end modifications (e.g. saccharides). If there are several spacers, they can be the same or different from one another.

For coupling the bisubstituted alkyne building blocks to the CH-acidic compounds, it has been found to be preferred in a polar, aprotic organic solvent (for example DMF, DMSO) under basic conditions (for example with the addition of NaH, sodium ethylate, deazabicycloundecane (DBU), LIH , with NaH being preferred). In general, the repeated reaction between a CH-acidic compound and an unsubstituted alkynyl bromide has already been described by RK Singh in Synthesis 1985, 54. However, this reaction takes place under phase transfer catalysis. All organic substances are in one organic -13/6

4

Phase, the necessary base (e.g. hydroxide) is dissolved in water. A suspension is produced by vigorous stirring, the hydroxide being able to be “dragged” into the organic phase with the aid of a suitable counterion (usually tetrabutylammonium = phase transfer catalyst) and a proton can be abstracted there. Since in this reaction the sodium hydroxide solution will fan in at least 10-20

Excess is used in the alkylation of e.g. Malonestem is not a monosubstituted species, but almost always only isolates the bialkylated species.

The conditions in which the components react with one another can be determined by a person skilled in the art. The ratio of the components is preferably:

CH-acidic compound: alkynyl halide: base (e.g. NaH) = 1:> 4:> 4.5

The reaction times can be between 2 and 24, preferably between 5 and 20, very preferably 8 to 15 hours.

The reaction temperatures are between 0 ° C and 60 ° C, preferably between 20 and 40 ° C, very preferably at room temperature to about 30 ° C.

In the course of the reaction, less alkylated species need not be separated if 2 (e.g. starting from the malonic ester) or 4 (starting from acetone dicarboxylic acid ester) identical residues are to be added. Then there is a so-called exhaustive alkylation, which can take place as a "one-pot reaction". However, if species with different dendrimer arms are to be synthesized, cleaning should be carried out after each alkylation step. This purification, as well as the purification of any intermediate or end products, can be carried out by means of column chromatography, e.g. over silica gel 60 (Machery-Nagel) with

Petroleum ether / ethyl acetate as eluent.

Preferred compounds according to the inventive method -12/6

5 are produced or reacted, the compounds shown in the following examples are 43α, 43ß, 44, 47, 48, 49 and 50.

Depending on the choice of the starting compounds, the process according to the invention offers various possibilities: When choosing an asymmetrical C-H-acidic

Compounds (e.g. acetoacetic esters) are able to control deprotonation and alkylation, so that little by little four individual and also differently substituted alkynyl halides can be coupled regioselectively. This offers the possibility of different spacer lengths and e.g. Use sugar groups. The configuration at the anomeric center is previously in the

Linkage of the sugar building block to the alkynyl bromide is fixed so that anomerically pure compounds can be obtained. After splitting off any ester groups that may be present, the keto group is converted to the alcohol function, so that a further spacer can be introduced, to which e.g. a desired active ingredient can be coupled. Such a reaction scheme is in

Fig. 3 shown.

Dendrimers produced according to the invention are notable for a number of advantageous properties. They are biodegradable. Therefore, they are easy to dispose of. Furthermore, they are essentially renewable

Raw materials. This protects fossil raw materials and keeps the CO ₂ balance neutral. Furthermore, the dendrimers according to the invention are present in precisely defined structures, ie there are no defects and / or inter- or intramolecular bonds. Furthermore, dendrimers according to the invention have chiral C atoms. In addition, due to their structure, they can be chemical

Tie connections well and release them again under suitable conditions. Furthermore, dendrimers according to the invention are able to enter into elective interactions with sugar-specific receptors and thus e.g. bind to viruses, bacteria and cells.

Therefore, dendrimers produced according to the invention are ideally suited as column material for separating substances from mixtures of products, in particular for separating racemates into enantiomers. Furthermore, they can due to their interactions with receptors for the affinity chromatographic isolation of lectins and other glycoproteins and as cell adhesion inhibitors, for example viruses and bacteria for infection protection.

In addition, dendrimers produced according to the invention can be provided for a large number of other uses. For example, they can be used as catalysts in enatioselective synthesis. They are also suitable in the medical field, e.g. as a carrier of medicinal substances, in particular for use in depot medication and for the targeted injection of active substances into target cells (drug targeting). Furthermore, they can be used to prevent rejection reactions in organ transplants. Dendrimers according to the invention can also be used for the surface coating of aqueous media and as micelles. Furthermore, they can, especially if they carry functional groups such as amino groups in the outermost shell

Transfection, as multi-antigenic determinants, artificial vaccines or enzyme models in analogy to cyclodextrins. Furthermore, dendrimers according to the invention which are conjugated to solid phases, in particular derivatives of inositol, can be used for the treatment of drinking water contaminated with bacteria. Furthermore, dendrimers according to the invention, if they are linked to dyes, can be used to label lectins in histochemical and cytochemical processes.

Brief description of the drawings:

Fig. 1: General reaction scheme

Fig. 2: Structure of a dendrimeric structure starting from a galactose-modified alkynyl bromide and acetone dicarboxylic acid ester

Fig. 3: Structure of a dendrimeric structure based on a sugar-modified alkynyl bromide and acetoacetic ester -10/6

7 The following examples illustrate the invention.

Example 1: Preparation of 1 -Brom ^ a'jS '^'je'-tetra-O-benzyl-α-D-glucopyranosyl] -but-2-in (43) and

benzy! -ß-D-glucopyranosyl] -but-2-in (43ß)

1.23 g (1.80 mmol) 2,3,4,6-tetra-O-benzyl-α (or β-) -D-glucopyranosyl-trichloroacetimidate [Schmidt et al., Angew. Chem. 1980, 92, 763] and 373 mg (2.50 mmol) of 1-bromobut-2-yn-4-ol were dissolved in 16 ml of dichloromethane under argon and cooled to -30 ° C. 60 μl (72 mg, 0.32 mmol) of trimethylsilyltrifluoromethanesulfonate was added dropwise over a septum. The mixture was allowed to warm to RT overnight with stirring. The reaction mixture was shaken with saturated sodium bicarbonate solution and the organic phase was separated off. The aqueous phase was extracted twice more with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. It was concentrated and the residue was removed using

Column chromatography separated.

SC: KG, PE / EE (17: 3)

43α:

Yield: 501 mg (41%)

DC: R _f (PE / EE 17: 3): 0.17

¹ H-NMR: δ _H (250.13 MHz; CDCI ₃ ): 3.57-3.80, 3.94-4.03 (4H, 2H, each m, H-2, H-3, H-4, H-5, H-6) ; 3.89 (2H, t, H-10); 4.30 (2H, t, H-7); 4.43-5.00 (8H, m, H-11a ... d); 5.04 (1H, d, H-1); 7.11-7.39 (20H, m, H-13a ... d, H-14a ... d, H-15a ... d), J _7.10 = 1.9 Hz, J _1ι2 = 3.6 Hz

¹³ C NMR: δ _c (62.90 MHz; CDCI ₃ ): 14.0 (C-10); 54.7 (C-7); 68.4 (C-6); 70.7, 77.5, 79.3, 81.6 (C-2, C-3, C-4, C-5); 72.9, 73.4, 75.0, 75.7 (C-11a ... d); 81.5, 82.1 (C-8, C-9); 95.4 (C-1); 127.5, 127.6, 127.6, 127.8, 127.9, 128.1, 128.3, 128.4 (C-13a ... d, C-14a ... d, C-15a ... d); 137.8, 137.9, 138.2, 138.7 (C-12a ... d) 11d-15d

HR-MS (FAB): Calculated for C ₃ 8H39 ⁸ BrO ₆ Na [M + Na ⁺ ]: 695.181 Found: 695.181 Calculated for C ₃₈ H39 ⁷⁹ BrOeNa [M + Na *]: 693.182 Found: 693.182

43ß:

Yield: 392 mg (32%)

DC: R _f (PE / EE 17: 3): 0.20

¹ H NMR: δ _H (250.13 MHz; CDCI ₃ ): 3.43-3.76 (6H, m. H-2, H-3, H-4, H-5, H-6); 3.89 (2H, t, H-10); 4.46-4.97 (11H. M, H-1, H-7, H-11a ... d); 7.12-7.40 (20H, m, H-

13a. "D, H-14a ... d, H-15a ... d); J _{7> 10} = 2.0 Hz

13, C NMR: δ _c (62.90 MHz; CDCl ₃ ): 14.0 (C-10); 56.3 (C-7); 68.8 (C-6); 73.5, 74.7, 74.9,

75.6 (C-11a ... d); 74.9, 77.6. 82.0, 84.6 (C-2, C-3, C-4, C-5); 81.7. 82.0 (C-8,

C-9); 101.6 (C-1); 127.6, 127.6, 127.6, 127.7, 127.7, 127.8, 127.9, 128.2.

128.3 (C-13a ... d, C-14a ... d, C-15a ... d); 138.1. 138.4, 138-6 (C-12a ... d) 8a

C ₃₈ H ₃₉ BrO ₆ M = 672.6

HR- S (FAB): Calculated for C ₃₈ H ₃₉ ⁷⁹ BrO ₆ Na [M + Na ⁺ ]: 693.183 Found: 693.181 Calculated for C ₃₈ H ₃₉ ⁸¹ BrO ₆ Na [M + Na ⁺ ]: 695.181 Found: δ ^. lδS

Example 2: Preparation of l-Bro - -t 'jS' ^ '- β'-tetra ^ OJ-benzyl-α-D-galactopyranosyl] -but-2-in (44) 3.51 g (5.12 mmol) [2, 3, 4, 6-tetra- (O) -benzy! -Ss-D-galactogyranosyl] - trichloroacetim.dat [Schmidt 1980] and 879 mg (10.2 mmol) of 2-butyne-1, 4-diol were in 15 ml abs , Acetonitrile suspended. The mixture was cooled to 15 ° C. and 150 l (~ 184 mg, 0.82 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise. After thirty minutes

b rach mandie R ea cti ondu rc h Addition of 250 mgfe st em sodium bicarbonate. After a further 30 minutes, the mixture was allowed to warm to room temperature and filtered. The filtrate was concentrated on a rotary evaporator and the residue was purified by column chromatography over silica gel with PE / EE 7: 3. The mixture of the two anomeric products was obtained as a colorless oil with a mass of 2.55 g, the R value was 0.21 on TLC with PE / EE 2: 1. As expected, the signals for [M + H] ⁺ , [M + NH4f and [M + Na] ^{+ were} found in the ESI mass spectrum for the calculated molar mass M = 608.7 of the intermediate.

307 mg of the intermediate were abs in 3 ml. CH ₂ CI ₂ dissolved. 327 mg (0.986 mmol) of tetrabromomethane were first added to this solution and, after its dissolution, 318 mg (1.21 mmol) of triphenylphosphine were added in portions in solid form over a period of 10 minutes. The mixture was stirred for 24 hours and then concentrated on a rotary evaporator. The residue was mixed with diethyl ether and stirred intensively for 30 min. The precipitate was filtered off and the filtrate was concentrated. The purification was carried out by means of column chromatography. Only a small part of the eluate contained pure product [DC: R _f (PE / Et ₂ O 8: 2): 0.09], the main part formed mixed fractions with a by-product, presumably with the corresponding cc anomer [DC: R ^ (PE / E ^ Ö 8: 2): 0.075], which were rejected.

Yield: 56.0 mg (14% over two stages)

TLC: R / (PE / Et ₂ O 8: 2): 0.09

1H-NMR: δ _H (250.13 MHz; CDC1 ₃ ): 3.51-3.60, 3.79-3.89 (each 4H, each m, H-2, H-3, H-4, H- 5, H-7, H- 10); 4.40-4.79, 4.91-4.96 (11H, each m, Hl, H-6, Hl la ... d); 7.27-7.42 (20H, m, H-13a ... d, H-14a ... d ₅ H-15a ... d)

13 'C-NMR: δ _c (62.90 MHz; CDC1 ₃ ): 14.1 (C-10); 56.0 (C-7); 68.7 (C-6); 73.1, 73.5, 74.4, 75.0 (C-lla ... d); 73.4, 73.4, 79.2, 82.1 (C-2, C-3, C-4, C-5); 81.4, 82.4 (C-8, C-9); 101.7 (Cl); 127.5, 127.7, 127.8, 128.1, 128.2, 128.2, 128.3, 128.4 (C-13a ... d, C-14a ... d, C-15a ... d); 137.8, 138.4, 138.5, 138.7 (C-12a ... d) 9a

C ₃₈ H ₃₉ BrO ₆ M = 672.6

HR-MS (FAB): Calculated for C ₃₈ H4 ₀ ⁷⁹ BrO ₆ [M + H] ⁺ : 671.201 Found: 671.193 Calculated for C ₃₈ H ₄₀ ⁸¹ BrO ₆ [M + H] ⁺ : 673.199 Found: 673.199

Example 3: 2,2-bis [4 ^, - (2 ", 3 ^" , 4 ", 6" -tetra- (O) -benzyl-σ-D-glucosy-but-2 ^, -inyl] - malonic acid - tert-butyl ester (47)

54 mg (80 μmol) 1-bromo-4- [2 ', 3', 4 ', 6'-tetra- (O) -benzyl-α-D-glucosyl] -but-2-in 43 and 6.9 mg ( 32 / mol) malonic acid di-tert-butyl ester were dissolved in 0.5 ml DMF. 3.2 was added. mg 60% NaH suspension (80 / mol) in solid form and allowed to stir at RT for 16 hours. The reaction was stopped by adding 2 ml of water and 2 ml of diethyl ether. The organic phase was separated off and the aqueous phase was extracted twice more with diethyl ether. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. After spinning in, the residue was purified by column chromatography. 10

Yield: 25.1 mg (56%)

SC: KG, PE / EE, 5: 1

DC: R _f (PE / EE 5: 1): 0.24

¹ H NMR: δ _H (250.13 MHz; CDCI ₃ ): 1.43 (18H, s, H-14); 2.92 (4H, m, H-10); 3.56-3.99 (10H, 2H, each m, H-2, H-3, H-4, H-5, H-6); 4.18 (4H. M, H-7); 4.42-4.98 (16H, m, _ H-11a ... d); 5.04 (2H, d, H-1); 7.11-7.39 (20H, m, H-13a ... d, H-14a ... d, H-15a ... d); J _1t2 = 3.6 Hz

¹³ C NMR: δ _c (62.90 MHz; CDCI ₃ ): 22.9 (C-10); 27.8, (C-14), 54.6 (C-7); 57.2 (C-11); 68.4 (C-6); 70.6, 77.5, 79.4, 81.9 (C-2, C-3, C-4, C-5); 72.7, 73.5, 74.9, 75.6 (C-11a ... d); 78.3, 81.6, 82.1 (C-8, C-9, C-13); 94.8 (C-1); 127.5, 127.5, 127.6, 127.8, 127.8, 127.9, 128.1, 128.3, 128.3, 128.3 (C-13a ... d, C-14a ... d. C- 15a ... d); 138.0, 138.1, 138.3, 138.8 (C-12ä ... d), 167.8 (C-12)

15d-19d

C ₈₇ H ₉₆ 0 ₁₆ M = 1397.7

HR-MS (FAB): Calculated for C _B7 H _9S 0 ₁₆ Na [M + Na] ⁺ : 1419.660 Found: 1419 664 11

Example 4: Preparation of 2,2-bis [4'-α-D-glucopyranosyI-butyl] - di-tert-butyl malonic acid (48) 20.2 mg (14.5 // mol) 2,2-bis [4 '- (2nd ", 3", 4 ", 6" -Tetra- (O) -benzyl-α-D-glucosyl) -but-2'-inyl] malonic acid di-tert-butyl ester 47 and 6.9 mg of 20% Pd / C were suspended in 1.0 ml acetone / water (9: 1) under a hydrogen atmosphere. The mixture was stirred at RT for 16 hours. After thoroughly flushing the flask with argon, the reaction mixture was filtered through a membrane filter and the filtrate was concentrated on a rotary evaporator. The residue could be purified by filtration through silica gel using methanol as the eluent. A colorless oil was isolated.

Yield: 9.8 mg (99%)

SC: KG, EE / MeOH, 4: 1

TLC: R _f (EE / MeOH 4: 1): 0.19

¹ H NMR: δ _H (250.13 MHz; CD ₃ OD): 1.20-1.29, 1.60-1.79 (12H, each m, H-8, H-9, H-10);

1.43 (18H, s, H-14); 3.22-3.81 (16H, m, H-2, H-3, H-4, H-5, H-6, H-7); 4.75

(2H, d, H-1); J., = 3.6 Hz

¹³ C NMR: δ _c (62.90 MHz; CD ₃ OD): 21.9, 31.1, 33.0 (C-8, C-9, C-10); 28.3 (C-14); 59.8 (C-11); 62.7 (C-6); 68.9 (C-7); 71.9 (C-3); 73.6, 73.7 (C-2, C-5); 75.2 (C-4); ~ 82.4 (C-13); 100.2 (C-1); 172.6 (C-12)

C ₃ ιH ₅₆ O ₁₆ M = 684.8

HR-MS (FAB): Calculate for C ₃₁ H ₅₆ θ ₁₆ Na [M + Na] ⁺ : 707.347 Found: 707.350 12

Example 5: Preparation of 2,2,4,4-tetrakis [4 ^, - (2 ", 3", 4 ", 6" -Tetra- (O) -benzyl-cr-D-glucapyranosyl) -but-2 ' -inyl] -3-oxoglutaric acid di-tert-butyl ester (49)

90 mg (134 / mol) 1-bromo-4- [2 ', 3', 4 ', 6'-tetra- (0) -benzyl-α-D-glucosyl] -but-2-in 43 and 5.7 mg (22 / mol) 3-oxoglutaric acid di-tert-butyl ester was dissolved in 0.5 ml DMF. 4.6 mg of 60% NaH suspension (110 // mol) in solid form were added and the mixture was stirred at RT for 24 hours. The reaction was stopped by adding 2 ml of water and 2 ml of diethyl ether. The organic phase was separated off and the aqueous phase was extracted twice with diethyl ether. The contaminated organic extracts were washed with water and dried over anhydrous sodium sulfate. After spinning in, the residue was purified by column chromatography.

Yield: 19.8 mg (33%)

SC: KG, PE / EE, 4: 1

DC: R _f (PE / EE 4: 1): 0.12

¹ H NMR: δ _H (250.13 MHz; CDCI ₃ ): 1.44 (18H, s, H-14); 2.91-3.15 (8H, m, H-10, H-10a); 3.55-3.97 (20H, 4H, each m, H-2, H-2a, H-3, H-3a, H-4, H-4a, H-5, H-5a, H-6, H-6a ); 4.15 (4H, m, H-7, H-7a); 4.39-4.96 (32H, m, H-11a ... h); 5.05, 5.06 (each 2H, each d, H-1); 7.09-7.37 (80H, m, H-13a ... h, H-14a ... h, H-15a ... h); J _{1 | 2} = 3.3 Hz

13 C NMR: δ _c (62.90 MHz; CDCI ₃ ): 24.7, 24.8 (C-10, C10a); 27.8, (C-15), 54.5 (C-7); 62.6 (C-11); 68.5 (C-6); 70.6, 77.5, 79.4, 81.9 (C-2, C-2a, C-3, C-3a, C-4, C-4a,

C-5, C-5a); 72.5, 73.5, 74.9, 75.6 (C-16a ... h); 79.2, 79.2, 81.6, 81.7 (C-8, C-8a, C-9, C-9a); 83.9 (C-14); 94.8 (C-1, C-1a); 127.5, 127.5, 127.6, 127.8, 127.8, 127.9, 128.0, 128.3, 128.3, ^" 128.3, 128.4 (C-13a ... h, C-14a ... h, C-15a ... h); 138.0, 138.1, 138.4, 138.9 (C-12a ... h), 167.6 (C-13); 197.0 (C-12) 13

C ₁₆₅ H ₁₇₄ O ₂₉ M = 2621.4

MS (ESI): Calculated for Cι ₆₅ H ₁₇₄ O ₂₉ Na [M + Na ⁺ ]: 2644.4 Found: 2644.2

Example 6: Preparation of 2 ₅ 2,4,4-tetrakis [4 '- (»- D-glucopyranosyl) butyl] -3-oxoglutaric acid di-tert-butyl ester (50) 17.2 mg (6.56 mol) 2,2,4 , 4-TetrakisI4 '- (2 ", 3", 4 ", 6" -Tetra- (0 -benzyl- -D-glucopyranosyl) -but-2'-ynyl] -3-oxoglutaric acid di-tert-butyl ester (49 ) and 5.8 mg of 20% Pd / C were suspended under a hydrogen atmosphere in 1.0 ml of acetone / water (9: 1) and reacted and worked up as described in regulation 48. The residue was purified by column chromatography, and a colorless oil was isolated. 14

Yield: 2.1 mg (27%)

SC: KG, PE / EE, 2: 1

DC: R _f (PE / EE 2: 1): 0.15

¹ H - NMR: - δ _H (250.13 MHz; CD ₃ OD): 1.20-1.37, 1.58-1.63 (24H, each m, H-8, H-8a, H-9, H- 9a, H-10, H-10a); 1.45 (18H, s, H-15); 3.22-3.81 (16H, m, H-2, H-2a, H-3, H- 3a, H-4, H-4a, H-5, H-5a, H-δ, H-6a, H- 7, H-7a); Signal for H-1 and H-1a, expected at = 4.75, is probably covered by the strong solvent signal at δ = 4.78

¹³ C NMR: δ _c (62.90 MHz; CD ₃ OD): 22.3, 31.3, 34.1 (C-8, C-9, C-10); 28.6 (C-15); 62.9 (C-6); 66.6 (C-11); 69.1 (C-7); 72.0 (C-3); 73.8, 73.8 (C-2, C-5); 75.3 (C-4); 83.4 (C-14); 100.3 (C-1); 172.8 (C-13), 208.6 (C-12)

C- ₅₃ H ₉₄ Ö ₂₉ M = 1195.3

HR-MS (FAB): Calculated for CsaH ^ OasNa [M + Na ⁺ ]: 1217.578 Found: 1217.581

Claims

15

claims

1) Process for the production of dendritic structures comprising the

Reaction of an at least bisubstituted alkynyl halide with a C-H-acidic carbonyl compound in the presence of a base.

2) The method of claim 1, wherein the base is NaH, sodium ethylate, DBU or LiH.

3) Process according to claim 1 or 2, wherein the C-H-acidic carbonyl compound is diethyl acetone dicarboxylate, acetoacetic ester, diethyl malonate, di (2-trimethylsilylethyl) acetone dicarboxylate or di-t-butyl acetone dicarbonate.

4) Method according to claim 1 or 2, wherein the at least bisubstituted alkynyl halide is derived from 1-bromo-2-butyn-4-ol or 1-bromo-2-hexin-6-ol.

5) Process according to claim 1 or 2, wherein the at least bisubstituted alkynyl halide has the following structure:

Hal-CH ₂ -C≡CR with R = benzoyl, ethyl, tert-butyl, benzyl, silyl group, active pharmaceutical ingredients, saccharide

6) Method according to one of claims 1 to 5, wherein the reaction takes place in a polar, aprotic, organic solvent.

7) Process according to one of claims 1 to 6, wherein the components C-H-acidic carbonyl compound, alkynyl halide and base are reacted in a ratio of 1:> 4:> 4.5.