MXPA00001753A - Process for the preparation of organic azides - Google Patents

Abstract

A process for the addition of an azide function to an organic compound in which process a mixture is prepared by adding an epoxide-derivative of the organic compound and an alkali metal azide salt to a solvent is described. The mixture is heated to a reaction temperature at which the epoxide-derivative and the azide can react to form an azide derivative of the organic compound. An amount, near equimolar to the epoxide derivative, of a (1-6C)alkyl-(2-4C)carboxylic acid ester having a boiling point above the reaction temperature is added to the mixture before and/or during the reaction.

Description

PROCESS FOR THE PREPARATION OF ORGANIC AZIDES DESCRIPTIVE MEMORY The invention relates to a process for the addition of an azide function to an organic compound. In this process, an epoxide derivative of the organic compound and an alkali metal azide salt react in a solvent to form an azide derivative of the organic compound. An azide function is often introduced into an organic molecule, in particular a carbohydrate, during a multi-step synthesis of compounds with amino groups. The introduction of the azide function can be effected either by azide substitution of an appropriate leaving group, such as tosylate, mesylate or chloride, or by the addition of the azide anion to an epoxide. For example, azidohydrins, potential precursors of 1,2-aminoalcohols, can be prepared from epoxides by reaction with an alkali metal azide, under alkaline or acidic conditions. In most processes known in the art for the addition of azide to an epoxide, the process is carried out in a polar organic solvent at a temperature of about 100-110 ° C, in combination with a buffering system such as ammonium chloride , ammonium sulfate or tri-isopropylbenzenesulfonic acid / 2,6-lutidine (Van Boeckel et al., J.

Carbohydr. Chem. 1985, 4, 293-321). A problem encountered in these procedures is that secondary reactions can occur due to alkaline or acidic conditions, which lead to isomerization, epimerization and rearrangement. Another serious disadvantage of the use of an ammonium salt is that an ammonium azide is formed, which is considered an explosive compound, and when using ammonium chloride, the chloride can also be added to the epoxide instead of the azide. The use of buffers consisting of a mixture of an organic base and an acid for pH control, can result in the formation of the hydrazoic acid. This is a highly toxic and explosive gas. In general, reactions with alkali metal azides can not be carried out in a stainless steel reactor, because there is a possibility that heavy metal azides, such as chromium or nickel azide, are formed on contact with the walls of the reactor. These heavy metal azides are explosive in dry form. In addition, the azide ion has the same corrosive properties as, for example, the chloride or bromide ion. On the other hand, in a glass-lined reactor, severe corrosion of the glass coating also occurs at temperatures of 100-110 ° C. In particular, this occurs under basic conditions when, for example, by using sodium azide in water and dimethylformamide, the pH may rise to values of more than 12 due to the formation of sodium hydroxide. It has now been found that one or more of the mentioned disadvantages of the known processes for the addition of an azide function to an organic compound can be avoided if an amount, close to the equimolar with the epoxide derivative, of an acid ester (1 - 6C) (2-4C) alkylcarboxylic having a boiling point above the reaction temperature is added to the reaction mixture before and / or during the reaction. The term (1-6C) alkyl refers to a linear or branched alkyl group having 1-6 carbon atoms and (2-4C) carboxylic acid refers to a linear or branched carboxylic acid having 2-4 carbon atoms . The presence of this ester in the reaction mixture allows the maintenance of the pH within a reasonable range during the formation of the organic azide. The ester is saponified by the hydroxide ions generated during the reaction, and in this way the pH is kept under 10. Using this procedure, the azide addition reaction can be carried out safely in a glass-lined reactor, without acid formation hydrazoic and without corrosion of the glass layer of the reactor wall. Esters having a boiling point above the reaction temperature can be used. The boiling point must be greater than this temperature, because otherwise the ester would boil, leaving the reaction mixture. Examples of suitable esters are (1-6C) alkylformiates, (1 -5C) alkylacetates, (1-4C) alkylpropionates, (1 -3C) alkylbutyrates, butyl acetate being a preferred ester. The reaction mixture is heated to a reaction temperature at which the epoxide derivative and the azide can react to form an azide derivative of the organic compound. Usually, the reaction temperature is between 60 and 120 ° C. Preferably, the reaction temperature is maintained until the reaction is complete. The molar ratio between the aggregate amount of ester and the aggregate amount of the epoxide during the reaction should be close to the equimolar with the epoxide derivative. Usually, close to the equimolar is a ratio in the range of 0.9 to 1.1. A ratio of 1.0 is preferred. A ratio of less than 0.9 could eventually allow the pH to reach a value of 12, with negative consequences for the glass coating of the reactor, and a ratio of more than 1.1 could lead to the formation of alkanoic acid, with which alkali metal azide can generate hydrazoic acid, which is volatile, toxic and explosive. The ester can be added to the reaction mixture before the start of the reaction or during the reaction, or before and also during the reaction, although for practical reasons it is preferable to add the ester before the start of the reaction. The process of this invention can be used for the preparation of an azide derivative adjacent to a hydroxyl function of any organic compound capable of carrying an epoxide function. Examples of organic compounds that carry an epoxide function for the process are styrene oxide, 2,3-epoxybutane, indene oxide, but the preferred organic compounds are carbohydrate derivatives with an epoxide function. The use in the process of epoxy derivatives of 1,6: 2,3-dianhydro-4-O-phenylmethyl-β-D-mannopyranose or 1,6: 2,3-dianhydro-4-O- [2 , 3-bιO-phenylmethyl-4,6-O-phenylmethylidene-β-D-glucopyranosyl] -pD-mannopyranose or 1,6: 2,3-dianhydro-4-O- [2 , 3-bis-O-phenylmethyl-4,6-O- (1-methylethi di) - ß-D-glucopyranosyl] - ß-D-mannopyranose is more preferred. The other preferred use of the process is for the formation of 2-azido-2-deoxypyranose, which is a precursor for a glycosamine moiety in a glycosaminoglycan with antithrombotic properties. The alkali metal azides which may be used are lithium azide, potassium azide and sodium azide, with sodium azide being preferred. Many different types of solvents can be used in the process, for example ethanol, acetonitrile, dimethisulfoxide or hexamethylene. The use of a polar aprotic solvent, which is a solvent that is miscible with water, has a high dielectric constant (e >) is preferred.15) and is unable to donate hydrogen for the formation of hydrogen bonds. The preferred solvents are dimethylformamide, N-methylpyrrolidinone or dimethylacetamide. N-methylpyrrolidinone is most preferred to azidize carbohydrates. Preferably, water is added to the solvent in order to allow a higher concentration of water-soluble alkali metal azide salt in the reaction mixture. A considerable amount of water, up to a volume equal to that of the organic solvent, may be present in the reaction mixture. The addition reaction can usually be carried out at reaction temperatures in the range of 60-120 ° C, and preferably at 110 ° C. The completion of the addition reaction can be determined by measuring the components of the mixture, by methods generally known to one skilled in the art. The reaction can last from one hour to several days, depending on the reactivity of the organic epoxide and the various compounds in the mixture. When a substantial increase in the amount of organic azide formed during the reaction is not observed, or the amount of products of unwanted side reactions increases, the reaction is complete. The following example is described to illustrate the invention.

Legends of the figures. Figure 1: Reaction scheme for the synthesis of 1,6-anhydro-2-azido-4-O-phenylmethyl-2-deoxy-β-D-glucopyranose. Figure 2: Reaction diagrams for the addition of azide functions to the following epoxides: 1, 6: 2,3-dianhydro-4-O- [2,3-bis-O-phenylmethyl-4,6-O-phenylmethyl den-ß-D-glucopyranosyl] - ß-D-mannopyranose, 1,6: 2,3-dianhydro-4-O- [2,3-bis-O-phenylmethyl-4,6-O- (1 -methylethylidene) -β-D-glucopyranosyl] -β-D-mannopyranose, cyclohexene oxide, glycidyl isopropyl ether, styrene oxide and indene oxide.

Example Protocol for the addition of azide to 1,6: 2,3-dianhydro-4-O-phenylmethyl-β-D-mannopyranose. 10.88 kg of 1, 6: 2,3-dianhydro-4-O-phenylmethyl-β-D-mannopyranose in Figure 1) were dissolved in 54.4 L of 1-methyl-2-pyrrolidone in a coated reactor with glass. 6,113 mL of n-butyl acetate, 9,028 g of sodium azide and 38 L of water were added. The mixture was heated to 100 ° -110 ° C and stirred for 20 hours at 100 ° -110 ° C. The mixture was cooled to 25 ° C and water and ethyl acetate were added. The product was isolated from the reaction mixture by extraction with ethyl acetate. The ethyl acetate extract was evaporated at 60 ° C under vacuum while water was introduced, and the product was crystallized from water at 30 ° C. After filtering, washing and drying, the yield was 11.935 kg of 1,6-anhydro-2-azido-4-O-phenylmethyl-2-deoxy-β-D-glucopyranose (2 in Figure 1). TLC: toluene / ethyl acetate 70/30, RF: 0.35; melting point 98.4 ° C. Other identification: 1H NMR in CDCI3 and chemical shifts relative to TMS set at 0 parts per million: Position d M ulti plicity Hl 5.47 S H2 3.23 D H3 3.88-3.92 Ddd H4 3.38 m H5 4.62 Dd H6 3.70 Dd H6 '3.94 Dd CH2 of benzil 4.70 D Aromatic protons 7.29-7.40 m OH 2.43 D This reaction was carried out in the following epoxides according to the method described above: 1, 6: 2,3-dianhydro-4-O- [2,3-bis-O-pheni I met il-4, 6-O -fen i 1-methyl idén-ß-Dg lucopyranosyl] - ß-D-mannopyranose (3 in Figure 2), giving 1,6-anhydro-2-azido-4-O- [2,3-bis-O phenylmethyl-4,6-O-phenylmethylidene-β-D-glucopyranosyl] -2-deoxy-β-D-glucopyranose (4 in Figure 2). TLC: toluene / ethyl acetate 70/30 on silica, RF: 0.42. 1, 6: 2,3-dianhydro-4-O- [2,3-bis-O-phenylmethyl-4,6-O- (1-methyl-ethylidene) -β-D-glucopyranosyl] -β'-D -manopyranose (5_ in Figure 2), giving 1,6-anhydro-2-azido-4-O- [2,3-bis-O-phenylmethyl-4,6-O- (1-methylethylidene) -β- D-glucopyranosyl] -2-deoxy-β-D-glucopyranose (6_ in Figure 2). TLC: dichloromethane / acetone 90/10, RF: 0.50.

Cyclohexene oxide (7_ in Figure 2), 1 giving 2-azidocyclohexanol (8 in Figure 2). TLC: dichloromethane / methanol 60/40, RF: 0.93.

Glycidyl isopropyl ether (9 in Figure 2), giving, according to NMR, a 9: 1 mixture of 3-azido-2-hydroxypropyl isopropyl ether (1_0 in Figure 2) and 2-azido-3-hydroxypropyl isopropyl ether (1J_ in Figure 2). TLC: methanol, RF: 0.75.

Styrene oxide (12 in Figure 2), giving, according to NMR, a 1: 1 mixture of 2-azido-1-phenyl ethanol (13. in Figure 2) and 2-azido-2-phenyl ethanol ( 14 in Figure 2). TLC: dichloromethane / methanol 60/40, RF: 0.90 Indene oxide (1_5 in Figure 2), giving, according to NMR, 2-azidoindan-1-ol (1j6 in Figure 2) and / or 1-azidoindan-2-ol (17. in Figure 2) . TLC: toluene / ethyl acetate 1/1, RF: 0.74.

Claims (7)

1. A process for the addition of an azide function to an organic compound, in which process an epoxide derivative of the organic compound and an alkali metal azide salt react in a solvent to form an azide derivative of the organic compound, wherein an amount, close to the equimolar with the epoxide derivative of a (1-6C) alkyl- (2-4C) carboxylic acid ester having a boiling point above the reaction temperature is added to the reaction mixture before and / or during the reaction.

2. A process according to claim 1, wherein the epoxide derivative of the organic compound is selected from styrene oxide, 2,3-epoxybutane, indene oxide and an epoxy derivative of a carbohydrate.

3. A process according to claim 2, wherein the epoxide derivative of the organic compound is an epoxy derivative of a carbohydrate.

4. A process according to claim 3, wherein the epoxide derivative of a carbohydrate is 1,6: 2,3-dianhydro-4-O-phenylmethyl-β-D-mannopyranose or 1,6: 2,3- dianhydro-4-O- [2,3-bis-O-phenylmethyl-4,6-phenylmethylidene-β-D-glucopyranosyl] -β-D-mannopyranose or 1,6: 2,3-dianhydro-4- O- [2,3-bis-O-phenylmethyl-4,6-O- (1-methylene-ethyl-diene) -β-D-glucopyranosyl] -β-D-mannopyranose.

5. A process according to any of claims 1 to 4, wherein the reaction temperature is between 60 and 120 ° C.

6. A process according to any of claims 1 to 5, wherein the ester is butyl acetate.

7. A process according to any of claims 1 to 6, wherein water is added to the reaction mixture in an amount at most equal to the volume of the solvent.