WO2003040439A2

WO2003040439A2 - A process for crystallising oxonorleucinacetal

Info

Publication number: WO2003040439A2
Application number: PCT/EP2002/010568
Authority: WO
Inventors: Michael Schwarm; Jürgen Roos; Harald GRÖGER; Helge Werner; Corinna Rippel
Original assignee: Degussa Ag
Priority date: 2001-11-09
Filing date: 2002-09-20
Publication date: 2003-05-15
Also published as: AU2002340922A1; DE10155065A1; WO2003040439A3

Abstract

The present invention provides a process for crystallising oxonorleucinacetals (Ona) of the general formula (I). In particular, precipitation is performed from an aqueous medium with the addition of organic solvents which do not possess any free hydroxyl groups. This leads, after filtration etc., to a crystalline material with little residual moisture.

Description

A process for crystallising oxonorleucinacetal

The present invention provides a process for crystallising oxonorleucinacetals (Ona) of the general formula (I)

In particular, precipitation is performed from an aqueous medium with the addition of certain organic solvents which have a positive effect on the crystallisation characteristics .

Compounds of the formula (I) are suitable intermediates for preparing the pharmaceuticals described in US 5552397, WO 9738705 and in J. Med. Chem. 42, 305 (1999) .

L-oxonorleucinacetals have hitherto been isolated by precipitation from aqueous solutions after the addition of precipitation auxiliary agents such as methanol (WO 0004179, EP 919630), ethanol (WO 0003981) or isopropanol (EP 972845, EP 905257) . Also, fully evaporated products have been purified by recrystallisation from ethanol/water (WO 0003981) or treatment with methanol (Bioorg. Med. Chem. 1995, 3, 1237) or isopropanol (EP 972845) . Evaporation of the product solution to dryness or the use of toxic solvents, such as e.g. methanol, is a disadvantage when performing these processes on an industrial scale.

The development of a practical isolation process for the product (I) is of great importance to the industrial implementation of a process for preparing L-oxonorleucin- acetals. The criteria of chemical and optical purity, which must both be > 99 %, play a very important part here. The isolation yield to be produced also assumes a very high status. From a technical point of view, good filterability of the precipitated product is required. The product should have a low moisture content for the subsequent drying procedure. On the one hand this is an economic advantage, due to the shorter drying times involved, and on the other hand this is also a prerequisite for the production of high purity. The smaller the amount of solvent entrapped, the smaller the amounts of any contaminants present in the solution which can then get into the dried product. As a result of a short drying time, unnecessary thermal stress of the product is also avoided. The use of toxic precipitation agents should be avoided.

Thus, the object of the present invention was the provision of a further process for preparing oxonorleucinacetals which helps to overcome the disadvantages of the prior art and which can be performed effectively, from an economic and ecological point of view, on an industrial scale.

This object is achieved by a process in accordance with the features in Claim 1. Claims 2 to 5 provide advantageous variants of the process according to the invention.

As a result of adding a precipitation auxiliary agent which is a water-soluble organic solvent without free hydroxyl groups, in a process for crystallising an oxonorleucinacetal of the general formula (I)

in which

R represents (Cι-C₈) -al yl, (C₂-C₄) -alkylene, (Cβ-Ciβ) -aryl, (C₇-Cι₉)-aralkyl, (Cι-C₈) -acyl, from aqueous media, products are obtained in a surprisingly effective, but not less advantageous, manner, even on an industrial scale, which satisfy the requisite requirements with regard to yield (>90%) and purity (>99%, possibly >99%ee) . In particular, it can be regarded as surprising that, despite a relatively high water content in the precipitation solutions and the sometimes very high solubility of oxonorleucinacetals in water, high isolation yields can nevertheless be produced to a considerable extent using the process according to the invention.

In the context of the invention, suitable precipitation auxiliary agents are any organic solvents known to a person skilled in the art for use for this purpose. On the one hand they must have sufficient solubility in water to ensure precipitation from a homogeneous phase but, on the other hand, they must exhibit a low solubility for the oxonorleucinacetal used, such that as little as possible of this precipitation auxiliary agent has to be added in order to achieve complete precipitation.

Furthermore, preferred precipitation auxiliary agents are agents such as a water-soluble ketone or a water-soluble ether, wherein these should have a boiling point, if possible, of <85°C. This is relevant with regard to drying the product because the residual concentration of organic solvent can then be kept as low as possible after a short drying period under mild conditions. Therefore, precipitation auxiliary agents such as acetone, DME or THF are very particularly preferred in this connection.

In order to obtain as complete precipitation as possible, it is of particular advantage to concentrate the product solution by evaporation under vacuum before addition of the precipitation auxiliary agent. In order to thermally stress the compound to be isolated as little as possible, a person skilled in the art will perform the evaporation process at as low a temperature as possible. A temperature interval of 10°C to 90°C, preferably 40°C to 65°C, has proven suitable for this purpose.

Evaporation of the aqueous solution takes place, preferably before addition of the precipitation auxiliary agent, down to a concentration of 0.7 - 0.9 M, preferably down to the saturation limit for oxonorleucinacetal . Precipitated product can optionally be taken back into solution by renewed heating, but it can also be crystallised out of the suspension being produced.

Addition of the precipitation auxiliary agent preferably takes place at a temperature of 10°C to 60°C, particularly preferably at 20°C to 60°C, most preferably at 40°C to 60°C, or above that but below the boiling point of the mixture .

The process according to the invention is suitable for carrying out the preparation of oxonorleucinacetals on an industrial scale. It is of very particular advantage that the residual moisture remaining in the product after filtration is greatly reduced as compared with the process in the prior art, despite precipitation from an aqueous medium. This leads to the fact that, on the one hand the drying times required for the product can be reduced and means, on the other hand, that the product is contaminated with fewer secondary products from the precipitation solution, which helps to further increase the purity of the products . Obviously, the alcohols with free hydroxyl function used for this purpose in the prior art lead to more precipitation solvent sticking to the crystals during filtration. This could not have been deduced from the prior art .

Optionally, the solution of oxonorleucinacetal can be subjected to active carbon clarification before adding the precipitation auxiliary agent.

(Ci-Cβ) -alkyl groups are regarded to be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl , hexyl, heptyl or octyl together with all their structural isomers.

(Ci-Cs) -alkylenyl groups are understood to be alkyl bridges with 2 to 8 carbon atoms, wherein the substituents are each located in the 1 and n position, such as e.g. ethylenyl, propylenyl etc.

A (Cβ-Cis) -aryl group is understood to be an aromatic group with 6 to 18 carbon atoms. Particularly included here are compounds such as phenyl, naphthyl, anthryl, phenanthryl, biphenyl groups .

A (C₇-Cι₉) -aralkyl group is a (C₆-Cι₈) -aryl group bonded to the molecule via a (Ci-Cs) -alkyl group.

A (Cι-C₈)-acyl group is a (Cι-C₈) -alkyl group, which is bonded to the molecule via a C=0 function.

The structures of the compounds shown relate to all possible optical isomers, in particular the 2-S- or 2-R- isomer and the racemate. Experimental examples :

Example 1 - comparison:

518.5 ml (= 533.2 g) of an approximately 0.48 M aqueous solution of L-oxonorleucinethylenglykolacetal (47.3 g) are evaporated under vacuum at 55°C to a volume which corresponds to a weight of 277 g. After 20 minutes, 300 ml of isopropanol are added thereto, stirring is continued for a further 20 minutes and the mixture is then cooled to 10 °C. The precipitated solid is filtered off using a suction filter (with a filter diameter of 9 cm) and post- washed with 100 ml of a solution consisting of water and isopropanol in the ratio 1 : 4. The filtration time is > 45 minutes. The moist product obtained (50.0 g) has a moisture content of 24.3 %. The moist solid is then dried at 45 °C under vacuum, whereby the product (37.85 g) is produced with an isolation yield of 80 % and a purity of > 99 % .

Example 2 : 518.5 ml (= 533.2 g) of an approximately 0.48 M aqueous solution of L-oxonorleucinethylenglykolacetal (47.3 g) are evaporated under vacuum at 55°C to a volume which corresponds to a weight of 277 g. After 20 minutes, 300 ml of acetone are added thereto, stirring is continued for a further 20 minutes and then the mixture is cooled to 10°C. The precipitated solid is filtered off using a suction filter (with a filter diameter of 9 cm) and post-washed with 100 ml of a solution consisting of water and acetone in the ratio 1 : 4. The filtration time is 15 minutes. The moist product obtained (42.54 g) has a moisture content of 4.8%. The moist solid is then dried at 45°C under vacuum, whereby the product (40.5 g) is produced with an isolation yield of 86% and a purity of > 99 %. Example 3 :

A L-oxonorleucinethylenglykolacetal-containing solution is prepared in the presence of a whole cell catalyst via biotransformation. The procedure is based on the process described in patent document 000389 AM. This 0.206 M L-oxonorleucinethylenglykol-containing solution (2 1) , which contains secondary products, e.g. a proportion of salts, is evaporated under vacuum at 55°C to a volume of approx. 500 ml. After 30 minutes, 800 ml of acetone are added thereto and the mixture is then cooled to 10°C and stirring is continued for a further 30 minutes. The solid is filtered off using a suction filter (with a filter diameter of 11 cm) and post-washed with 250 ml of a solution consisting of water and acetone in the ratio 1 : 4. The filtration time is 15 minutes. The moist product obtained (69.05 g) has a moisture content of 7.7 %.

The moist solid is then dried at 45 °C under vacuum, whereby the product (64.1 g) is produced with an isolation yield of 82.2 % and a purity of > 99 %.

Example 4 :

500 ml (= 512 g) of a 0.5M aqueous solution of L-oxonorleucinethylenglykolacetal (47.3 g) are evaporated at 55 °C under vacuum to a volume which corresponds to a weight of 300 g. The temperature is then briefly raised to 60 °C in order to bring already precipitated L-oxonorleucinethylenglykolacetal back into solution. 450 ml of acetone are added thereto over the course of 30 minutes, stirring is continued for a further 30 minutes and then the mixture is cooled to 10 °C. The precipitated solid is filtered off using a suction filter (with a filter diameter of 9 cm) and post-washed with 100 ml of a solution consisting of water and acetone in the ratio 1:4. The filtration time is 12 minutes . The moist product obtained (45.7 g) has a moisture content of 4.6%.

The moist solid is then dried at 50 °C under vacuum, whereby the product (43.6 g) is produced with an isolation yield of 92.2%.

Example 5 :

500 ml (= 512 g) of a 0.5M aqueous solution of L-oxonorleucinethylenglykolacetal (47.3 g) is evaporated at 55 °C under vacuum to a volume which corresponds to a weight of 300 g. The temperature is then raised briefly to 60 °C in order to bring already precipitated L-oxonorleucinethylenglykolacetal back into solution. 450 ml of DME is added thereto over the course of 30 minutes, stirring is continued for a further 30 minutes and the mixture is then cooled to 10 °C. The precipitated solid is filtered off using a suction filter (with a filter diameter of 9 cm) and post-washed with 100 ml of a solution consisting of water and DME in the ratio 1:4. The filtration time is 7 minutes. The moist product obtained (45.7 g) has a moisture content of 3.2%.

The moist solid is then dried at 50 °C under vacuum, whereby the product (44.4g) is produced with an isolation yield of 93.9%.

Example 6

500 ml (= 512 g) of a 0.5M aqueous solution of L-oxonorleucinethylenglykolacetal (47.3 g) is evaporated at 55 °C under vacuum to a volume which corresponds to a weight of 300 g. The temperature is then raised briefly to 60 °C in order to bring already precipitated L-oxonorleucinethylenglykolacetal back into solution. 450 ml of THF is added thereto over the course of 30 minutes, stirring is continued for a further 30 minutes and the mixture then is cooled to 10 °C . The precipitated solid is filtered off using a suction filter (with a filter diameter of 9 cm) and post-washed with 100 ml of a solution consisting of water and THF in the ratio 1:4. The filtration time is 8 minutes. The moist product obtained (45.4 g) has a moisture content of 7.5%.

The moist solid is then dried at 50 °C under vacuum, whereby the product (42.0 g) is produced with an isolation yield of 88.8%.

Example 7 - comparison:

500 ml (= 512 g) of a 0.5M aqueous solution of L-oxonorleucinethylenglykolacetal (47.3 g) is evaporated at 55 °C under vacuum to a volume which corresponds to a weight of 300 g. The temperature is then raised briefly to 60 °C in order to bring already precipitated L-oxonorleucinethylenglykolacetal back into solution. 450 ml of isopropanol is added thereto over the course of 30 minutes, stirring is continued for a further 30 minutes and the mixture is then cooled to 10 °C. The precipitated solid is filtered off using a suction filter (with a filter diameter of 9 cm) and post-washed with a 100 ml of a solution consisting of water and isopropanol in the ratio 1:4. The filtration time is 30 minutes. The moist product obtained (44.3 g) has a moisture content of 9.7%.

The moist solid is then dried at 50 °C under vacuum, whereby the product (40.0 g) is produced with an isolation yield of 84.6%.

Claims

Claims :

1. A process for crystallising oxonorleucinacetals of the general formula (I)

in which

R represents (Cι-C₈) -alkyl, (C₂-C ) -alkylene, (Cβ-Ciβ)- aryl, (C₇-C₁₉) -aralkyl, (Cι-C₈) -acyl, from aqueous media, characterised in that a water-soluble organic solvent without free hydroxyl groups is added as precipitation auxiliary agent.

2. A process according to Claim 1, characterised in that a water-soluble ketone or a water-soluble ether with a boiling point <85°C is used as precipitation auxiliary agent .

3. A process according to Claim 1 and/or 2, characterised in that the aqueous oxonorleucinacetal solution is concentrated by evaporation under vacuum at temperatures of 10 °C to 90°C, preferably 40°C to 65 °C, before adding the precipitation auxiliary agent.

4. A process according to Claim 3, characterised in that the solution is concentrated by evaporation down to a concentration of 0.7 - 0.9 M, preferably down to the saturation limit of oxonorleucinacetal, before adding the precipitation auxiliary agent.

5. A process according to one or more of the preceding Claims, characterised in that the precipitation auxiliary agent is added at a temperature of 10°C to 60°C, preferably 40°C to 60°C.