MX2008006361A - Purification processes of echinocandin-type compounds - Google Patents

Abstract

The present invention provides a method of preparing and purifying echinocandin- type compounds, such as pneumocandin Bo, WF 11899 A, and echinocandin B. These compounds are fermentation products that are used to prepare semi-synthetic products such as the antifungal products Caspofungin, Mycafungin, and Anidulafungin.

Description

PURIFICATION PROCESSES FOR EQUINOCANDIN TYPE COMPOUNDS Field of the invention The invention comprises processes for purifying compounds of the echinocandin type including pneumocandin B0, WF 11899A and echinocandin B.

BACKGROUND OF THE INVENTION The pneumocandin B0, WF 11899A and the echinocandin B are all members of the echinocandin family, which have the general structure: They are fermentation products that are used to prepare semi-synthetic products, such as Caspofungin, Micafungin and Anidulafungin, respectively. All have fungicidal activity.

Caspofungin is the first of a new class of echinocandins and works by inhibiting the synthesis of the cell membrane. Caspofungin has the chemical name 1- [(4R, 5S) -5- [(2-aminoethyl) amino] -N2- (10,12-dimethyl-l-oxotetradecyl) -4-hydroxy-L-ornithine] -5 - [(3R) -3-hydroxy-L-ornithine] pneumocandin B0, CAS Registry Number 179463-17-3, and the following chemical structure (Formula I).

Formula I Caspofungin is disclosed in U.S. Patent No. 5,378,804. Caspofungin is marketed in the form of its diacetate salt in the United States by Merck & Co. , Inc. under the trade name CANCIDAS®. CANCIDAS® is administered intravenously for the treatment of infections such as Aspergillus and Candida and for the prevention of infections found in immunodeficient patients.

Anidulafungin is marketed in the United States by Pfizer under the brand name Eraxis® and is administered intravenously for the treatment of infections such as Candida.

Micafungin is marketed in the form of its sodium salt in the United States by Astellas under the brand name Mycamine ® and administered intravenously for the treatment of infections such as Candida.

The processes for the preparation of caspofungin consist in the use of pneumocandin. Pneumocandin is disclosed in U.S. Patent No. 5,194,377 and has the following chemical structure: Pneumocandin is prepared by fermentation reactions, where fermentation and mixed broths generally contain numerous byproducts that can be difficult to separate from the desired product. U.S. Patent No. 6,610,822 describes the purification of echinocandin-type compounds, such as pneumocandin, F 11899 and echinocandin B and performing various extraction operations, the first to remove non-polar impurities, the second to remove polar impurities. and then the "backward extraction" of the product, optionally, in a combination with the chromatographic purification. U.S. Patent No. 6,610,822 provides a long and time-consuming purification process.

U.S. Patent No. 5,021,403 describes a purification process of echinocandin-type compounds such as pneumocandin, WF 11899 and echinocandin B by performing various chromatographies. Therefore, this process is not suitable for large scale manufacturing, it is not economical and it consumes time.

U.S. Patent No. 6,506,726 and U.S. Patent No. 6,590,073 describe the purification of echinocandin-like compounds, especially echinocandin B deacylated by chromatography. The purified substances are echinocandin nuclea, which contain at least one amino group that can be protonated in the presence of an acid. Therefore, this process is not suitable for substances that do not have an amino group that is protonated, such as pneumocandin, WF 11899 and echinocandin B.

There is a need in the art for additional processes to purify compounds of the echinocandin type, using techniques that are viable for use on an industrial scale.

EXAMPLE OF THE INVENTION The invention comprises processes for purifying an echinocandin-like compound, including pneumocandins. In one embodiment, the invention comprises a process for purifying an echinocandin-type compound comprising: (a) extracting impurities from a whole broth having an echinocandin-like compound with at least one organic solvent immiscible with non-polar water or weakly polar to obtain a first two-phase system comprising an aqueous phase and an organic phase; (b) removing the organic phase to obtain the aqueous phase; (c) extracting the echinocandin-like compound from the aqueous phase with a second organic solvent immiscible with water to obtain a second two-phase system; and (d) recovering the purified echinocandin-type compound from the organic phase of the second two-phase system, wherein the water-immiscible organic solvents of steps (a) and (c) are different.

In another embodiment, the invention comprises a process for purify compounds of the echinocandin type comprising crystallize echinocandin type compounds using so minus an antisolvent.

In yet another embodiment, the invention comprises a process for purifying an echinocandin-type compound comprising: (a) extracting impurities from a whole broth having a compound of the echinocandin type with at least one organic solvent immiscible with non-polar or weakly polar water to obtain a first two-phase system comprising an aqueous phase and a organic phase; (b) remove the organic phase to obtain the phase watery (c) extract the echinocandin-like compound from the aqueous phase with a second organic solvent immiscible with water to obtain a second two-phase system; (d) recover the compound of the echinocandin type, and (e) crystallize the Echinocandin type compound using at least one antisolvent, where the organic solvent immiscible with water of steps (a) and (c) are different.

In one embodiment, the invention comprises a process for purify an echinocandin-type compound comprising "combining the echinocandin-type compound with at least an antisolvent and a solid carrier.

In another embodiment, the invention comprises a process for purifying an echinocandin-type compound comprising: (a) extracting the echinocandin-like compound from a fermentation broth or from a filtered mycelium obtained from a fermentation broth with an organic solvent immiscible with water to obtain a two-phase system comprising an aqueous phase and an organic phase; (b) recovering the echinocandin type compound; and (c) combining the echinocandin type compound with at least one antisolvent and a solid carrier to obtain a purified echinocandin type compound.

Brief Description of the Figures Figure 1 is a flow chart illustrating an embodiment of step purification processes.

Detailed Description of the Invention The invention comprises processes for purifying pneumocandin or other compounds of the echinocandin type. As used herein, unless otherwise defined, the term "Echinocandin-like compounds" refers to compounds having the following general structure including derivatives thereof: wherein R is hydrogen or -C (0) R '; R 'is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group which attached thereto at least one amino group which can be protonated in the presence of an acid; Ri is -H or -OH; R2 is -H or -CH3; R3 is -H, CH3, -CH2CONH2 or -CH2CH2NH2; R 4 is -H or -OH; R5 is -OH, -OP03H2, or -OS03H; R6 is -H or -OS03H, and R7 is -H or -CH3.

Preferably, R is linoleoyl, 10, 12-dimethyl myristoyl, or palmitoyl. Preferably Ri, R4 and R5 are OH. Preferably, R3 is Me, or CH2CONH2.

Preferably when R is linoleoyl, Rx, and R4 are OH, R3 and R7 are Me, and R6 is H, ie the compound is echinocandin B. Preferably, when R is 10, 12-dimethyl myristoyl, Ri, and R4 are OH , R3 is CH2CONH2, R5 is OH, and R6 and R are H, ie the compound is pneumocandin B0.

Preferably, when R is palmitoyl, Ri, and R4 are OH, R3 is CH2CONH2, R5 is OH, R6 is 0S03H, and R7 is CH3, ie the compound is F11899A.

Preferably, the Echinocandin-type compounds are pneumocandin B0, F-11899, and echinocandin. These products are not highly soluble in conventional solvents, such as esters, lower alcohols and water. Therefore, they are difficult to purify by conventional extractions. Accordingly, the processes known for their purification are generally complicated and inefficient, especially when handling large amounts of these compounds.

The present invention offers compounds for purifying Echinocandin-like compounds, which are suitable for any scale, including the industrial scale. These processes of the present invention are simple in that the steps of the process are not complicated, easy to manufacture in scale for an industrial scale process, and economical while providing echinocandin-like compounds of a purity that is sufficient for a new processing to obtain an active pharmaceutical ingredient such as for example the fungicides caspofungin, anidulafungin, and micafungin. The first process of the present invention uses the low solubility characteristic of Echinocandin-type compounds.

As used herein, unless otherwise mentioned, the term "water-immiscible solvent" refers to a solvent or mixture of solvents that when mixed with water does not form a single mixture but forms a system of at least two phases. Conversely, a "solvent miscible with water" refers to a solvent or a mixture of solvents that when mixed with water forms a single phase of solution.

As used herein, unless otherwise used, the term "solid carrier" refers to a material (compound) that is inert and that remains undissolved in the process solvents but is capable of forming a mix with the compound (s).

As used herein, unless otherwise mentioned herein, the term "non-polar" refers to organic solvents that have a polarity index of from 0 to 2.4. Examples of such solvents are toluene, heptane, hexane, octane and cyclohexane.

As used herein, unless otherwise mentioned, the term "weakly polar" refers to organic solvents having a polarity index of 2.4 to 5.1, which excludes organic solvents. Examples of such solvents are methyl ethyl ketone, acetone, diisopropyl ether, diethyl ether, isobutyl acetate, n-propyl acetate, ethyl acetate, dichloromethane, and isopropyl acetate. The polarity index can be measured according to Synder, J. Chromatographic science 16, 223-234 (1978).

In one embodiment, the invention comprises a process for purifying an echinocandin-type compound comprising: (a) extracting impurities from a whole broth having an echinocandin-like compound with at least one organic solvent immiscible with non-polar water or weakly polar to obtain a first two-phase system comprising an aqueous phase and an organic phase; (b) removing the organic phase to obtain the aqueous phase; (c) extracting the echinocandin-like compound from the aqueous phase with a second organic solvent immiscible with water to obtain a second two-phase system; and (d) recovering the purified echinocandin-type compound, wherein the water-immiscible organic solvents of steps (a) and (c) are different.

When the echinocandin-like compound is pneumocandin B0, the initial doped pneumocandin (such as pneumocandin in a fermentation broth) can be prepared, for example, by the process described in U.S. Patent No. 6,610,822.

Preferably, the echinocandin-type compound is present in the whole broth at a concentration of 0.2 to 15 g / L, more preferably 0.2 to 8 g / L. The concentration of the echinocandin-type compound in the fermentation broth can be determined by HPLC analysis.

In the process of the present invention, the fermentation broth having the echinocandin-type compound is combined with the organic solvent immiscible with non-polar or weakly polar water to obtain the first two-phase system. Generally, the two-phase system comprises impurities, such as vegetable oils, amino acids, and proteins of small molecular size in the organic phase immiscible with non-polar or weakly polar water and the echinocandin-type compound and the mycelium in the aqueous phase, which is the aqueous medium of the fermentation broth. Therefore, in some embodiments, the aqueous phase may also contain insoluble particles.

Accordingly, non-polar or weakly polar immiscible organic solvents include solvents wherein the echinocandin-type compound has low solubility. Preferably, non-polar or weakly polar immiscible organic solvents include, but are not limited to, aliphatic alkanes of C5_8, aromatic hydrocarbons of e-Br ethers of C4-8, and esters of C3-6. Preferably, the C5-8 aliphatic alkane is heptane, hexane, octane or cyclohexane. Preferably, the aromatic hydrocarbon of C-β is toluene. Preferably, the C4_8 ether is diethyl ether, diisopropyl ether or dibutyl ether. Preferably, the C 3-6 ester is isobutyl acetate, n-butyl acetate, n-propyl acetate, isopropyl acetate or ethyl acetate. More preferably, the organic solvent immiscible with non-polar or weakly polar water is iso-butyl acetate, n-butyl acetate, n-propyl acetate, isopropyl acetate or ethyl acetate.

In the process of the present invention, the amount of the organic solvent immiscible with non-polar or weakly polar water that is used to obtain a first two-phase system can be from 5% to 90% by volume of the whole broth, according to the efficiency of the separation of the two phases. If there is an efficient phase separation, 5% -25% is generally sufficient. However, if there is a non-optimal phase separation, 50% -90% should be used. Preferably, the amount of the water-immiscible solvent used is 10% to 50%, more preferably 30% to 50%, more preferably 50% by volume of the whole broth.

The extraction provides a purified fermentation broth, which is the aqueous phase of step (b). This phase is usually purified enough to continue the extraction process with only one additional extraction step.

The aqueous phase of step (b) is then extracted with a second solvent immiscible with water, to remove the echinocandin-like compound from the aqueous phase. This extraction provides the second two-phase system comprising the echinocandin-type compound in the organic phase immiscible with water, which is preferably a polar organic phase obtained with the extraction with an alcohol and called the organic phase, and the mycelium and the substances which are not soluble in water in the organic phase remain in the aqueous phase. Examples for substances that are not soluble in a polar organic phase are various amino acids and salts of amino acids, enzymes, and proteins. A second organic solvent immiscible with water of step (c) is one that has high affinity for the echinocandin-type compound. Preferably, the second organic solvent immiscible with water is an alcohol, more preferably a C 4-6 alcohol, still more preferably, a C 4-5 alcohol, more preferably, isobutanol or n-butanol.

The extraction of step (c) can be repeated to further increase the yield of the echinocandin-like compound in the organic phase. In a preferred embodiment of the present invention, the step of extraction (c) is repeated.

The echinocandin-like compound is then recovered from the organic phase by any method known in the art, such as by evaporating the solvent. The recovery provides a concentrate of the organic phase having the echinocandin type compound. The concentrate can be a concentrated solution or an oily residue of the echinocandin-type compound, referred to as a concentrated waste.

The obtained concentrated residue can then be purified by crystallizing the echinocandin-type compound using at least one antisolvent.

In one embodiment, the present invention provides a process for purifying echinocandin-type compounds comprising crystallizing echinocandin-like compounds using at least one antisolvent.

The crystallization comprises mixing the echinocandin-like compound with an antisolvent to precipitate the echinocandin-like compound. Preferably, the antisolvent is added to the echinocandin-type compound.

The initial echinocandin type compounds are preferably obtained from extractions of the fermentation broth. The extractions can be made, for example, by the process that is disclosed herein or by any other method known to one skilled in the art.

The initial echinocandin type compounds may be in the form of a concentrated residue, obtained by the process described above.

As used herein, the term "anti-solvent" refers to a liquid that is added to a mixture of a solvent and a solid to reduce the solubility of the solid in the solvent.

A suitable anti-solvent causes precipitation of the echinocandin-type compound. Accordingly, a suitable antisolvent is such that when the echinocandin-type compound has low solubility. Preferably, suitable antisolvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetone, acetonitrile (ACN), mixtures of acetonitrile with ethyl acetate and isobutyl acetate, and mixtures of acetonitrile with acetate of iso-butyl. The most preferred antisolvents are isobutyl acetate, n-butyl acetate, tert-butyl acetate, acetonitrile, acetone and isopropyl acetate and even more preferably, acetonitrile. Preferably, the amount of the antisolvent is added in a ratio of at least 2: 1 of the antisolvent: ester, more preferably from 5: 1 to 2: 1, even more preferably from 3: 1 to 2: 1 v / v, respectively .

In a preferred embodiment the antisolvent is acetonitrile and is present in an amount such that the ratio of acetonitrile: water is at least 2: 1 v / v, respectively. In another preferred embodiment, the antisolvent is acetone and is present in an amount such that the ratio of acetone: ester is at least 2: 1 v / v, respectively.

In some embodiments, when the antisolvent is ethyl acetate or isobutyl acetate, the precipitation also includes a cooling step or the addition of a second antisolvent, such as ACN or acetone, to induce precipitation. Said cooling step may be to cool the mixture of the concentrated waste and the antisolvent at a temperature of 5 ° C to -20 ° C, more preferably 5 ° C to 0 ° C.

In another embodiment, for example, when the antisolvent is ACN or acetone, the precipitation also comprises cooling to a temperature of 5 ° C to -20 ° C, more preferably 5 ° C to 0 ° C, to increase the yield of the product precipitate.

The precipitation provides a suspension, which can be maintained at said temperature for a sufficient period of time to increase the yield of the precipitated product. Preferably, the suspension is maintained for at least 15 minutes, more preferably for 10 hours to 24 hours, more preferably for 20 hours.

In another process of the invention, a solid carrier is used in the purification process, thereby eliminating the first extraction step where the impurities are extracted, as is needed for example in the process described above. In addition, a smaller amount of solvents is needed in the extraction step (s), and also in the crystallization step, making the process very attractive, especially for large scale manufacturing.

This process comprises the steps of (a) extracting the echinocandin-like compound from the fermentation broth or from a filtered mycelium obtained from a fermentation broth with an organic solvent immiscible with water to obtain a two-phase system having an aqueous phase and an organic phase; (b) recovering the echinocandin type compound; and (c) combining the echinocandin type compound with at least one antisolvent and a solid carrier to obtain a purified echinocandin type compound.

Initially, the fermentation broth is combined with a solvent immiscible with water to obtain a two-phase system. The organic solvent immiscible with water is that described above, preferably the organic solvent immiscible with water is an alcohol immiscible with water. In a preferred embodiment, the extraction is carried out at a pH of 2 to 8, preferably 5 to 7. When extracted at acidic pH, such as pH 2 to 4, extraction is preferably carried out while cooling and after the first cooling the fermentation broth and the solvent immiscible with polar water to avoid the decomposition of the product. Preferably, the cooling is at a temperature of 0 ° C to 10 ° C, more preferably 0 ° C to 5 ° C. Generally, the pH is adjusted to a range of 2 to 8 by adding a base or an acid, depending on the pH of the fermentation broth. Suitable bases are, for example, ammonium bases, such as ammonium hydroxide, or dilute aqueous solutions of alkaline base, such as sodium hydroxide. Suitable acids are, for example, acetic acids or dilute aqueous solutions of sulfuric acids.

The step of the extraction can be repeated to increase the yield of the echinocandin-like compound in the second organic phase immiscible with water. Preferably, the extraction is repeated at 2-4 extractions, more preferably a total of 3 extractions are preferred at this extraction step.

The echinocandin-like compound is then recovered from the organic phase by any method known in the art, such as by evaporating the solvent. Recovery provides a concentrate of the organic phase having the echinocandin type compound. The concentrate can be a concentrated solution or an oily residue of the echinocandin-like compound named in the present concentrated residue. This crude residue of the echinocandin-type compound can be obtained by stirring the solvent almost to dry to obtain a concentrate. Removal of the organic solvent immiscible with water can be repeated several times by adding an organic solvent immiscible with non-polar or weakly polar water, such as isobutyl acetate, and evaporating the solvents, wherein the organic solvent immiscible with non-polar or weakly polar water is different from the solvent immiscible with water from step (a) of the preceding process.

Optionally, the process comprises a further washing step of the obtained concentrate, before crystallizing the echinocandin-like compound by combining it with an antisolvent and a solid carrier as in step c). This washing step comprises combining the obtained concentrate with water. In a preferred embodiment, the washing comprises two steps, one using water having a pH of from 4 to 6.5, preferably from 4 to 4.5, and one second, using water having a pH of from 4 to 6.5, preferably from 6 to 6.5. In addition, when the concentrate obtained is cooled, for example at 5 ° C, water having a pH lower than 4, for example water having a pH of 3, can be used. Washes can remove approximately 20% to 50%. % by weight of solid waste that originated in the fermentation broth and may be present in the concentrate. In addition, the concentrate can be treated with activated carbon before crystallizing the echinocandin-like compound by combining it with an antisolvent and a solid carrier as in step c). This treatment comprises mixing activated carbon and the concentrate and then filtering the activated carbon.

The concentrate obtained can then be further purified by combining it with at least one antisolvent and a solid carrier to obtain a compound of the echinocandin-purified type.

In one embodiment, the invention comprises a process for purifying an echinocandin-type compound comprising combining the echinocandin-like compound with at least one antisolvent and a solid carrier. Preferably, the antisolvent and the solid carrier are added to the compound, of the echinocandin type.

Echinocandin-type compounds are preferably obtained from extractions of the fermentation broth. The extractions may be made, for example, by the processes disclosed herein or by any other method known to one skilled in the art.

The initial echinocandin type compounds may be in the form of a concentrated residue, obtained by the processes described above.

The precipitation of the echinocandin-type compound occurs on the solid carrier, therefore the echinocandin-type compound is absorbed on the solid carrier and consequently is separated from the impurities that are still present in the concentrate obtained in the steps of the process previous In the precipitation of the substance of interest with an antisolvent, when a smaller volume of the antisolvent is used, a high purity of the precipitated substance is obtained, but this smaller volume of the antisolvent also complicates its filtration. The solid carrier facilitates filtration of the precipitated substance that is otherwise difficult to filter. Suitable solid carriers include, but are not limited to, activated carbon, diatomaceous earth, wheat flour, corn starch, potato starch, bentonite, perlite, avicel, hydrophobic perlite, active lignite flour, carbons, cellulose products, and another solid product, which can be suspended in the solvent solution of the process of the present invention.

In this step of the process, a mixture is prepared by combining the solid carrier and the concentrate obtained in the previous step. The mixture is then combined with an anti-solvent. Preferably, a suitable anti-solvent is that described above in addition to isopropyl acetate and isobutyl acetate. Generally, after the addition of the antisolvent, a suspension is obtained.

The suspension is then filtered, to remove the solid carrier and the absorbed product.

The process also comprises suspending the filtered solid carrier and the absorbed product to remove traces of another liquid. The solvent used to create the suspension can be a single solvent, such as ACN or acetone or a mixture of two solvents, in both of which the echinocandin-type compound possesses low solubility. When a mixture of two solvents is used, the first solvent is one in which the impurities are soluble, such as isobutyl acetate, isopropyl acetate and ethyl acetate, octane and the second is acetonitrile or acetone.

In addition, the product and the solid carrier can be recovered from the suspension by any method known to one skilled in the art, such as, for example, by filtration and subsequent drying of the filtered solid product. Preferably, the product can be separated from the solid carrier by combining the complex of the solid carrier and the echinocandin-like compound with a solvent in which the product is soluble, as for example in alcohols, for example methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, in DMF, or DMSO. The solid carrier is then filtered to obtain the purified product. The filtered product containing the purified product can then be purified by any known precipitation or chromatography method.

The purified echinocandin type compound can be further used to prepare synthetic products, such as caspofungin, anidulafungin or micafungin.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from the treatment of the specification. The invention is further defined with reference to the following examples which describe in detail the processes of the invention. Although the examples focus on pneumocandin B0, WF 11899A and echinocandin B, one skilled in the art would recognize that processes can be adapted with little or no experimentation to purify other natural products in the echinocandin family. It will also be apparent to those skilled in the art that many modifications can be made to both the materials and methods, without departing from the scope of the invention.

Examples Example 1 Step a: Purification One kilogram of a fermentation broth containing pneumocandin B0 was combined with 0.5 liter of isobutyl acetate to form a two-phase system. The two phases were separated with a centrifuge. The isobutyl acetate phase was removed. All of the pneumocandin B0 remained in the purified fermentation broth.

The purified fermentation broth was then extracted with 500 ml of isobutanol. The extraction was then repeated with another 500 ml of iso-butanol. The resulting two iso-butanol phases were combined to obtain an iso-butanol phase of 1090 ml. The total yield of purification and extractions was approximately 100%.

Step b: Crystallization The isobutanol phase was divided into five 200 ml portions. The crude pneumocandin B0 was crystallized from each of the portions by the following processes. i) A 200 ml portion was concentrated to 3.5 g under reduced pressure. Then 17.5 ml of isobutyl acetate was added. The resulting solution was then cooled to 0 ° C-5 ° C. The solution was then allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 37%. ii) Another 200 ml portion was concentrated to 3.5 g under reduced pressure. Then 17.5 ml of acetonitrile was added. The resulting solution was then cooled to 0 ° C-5 ° C. The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 75%. iii) Another 200 ml portion was concentrated to 3.5 g under reduced pressure. Then another 17.5 ml of ethyl acetate was added. The resulting solution was then cooled to 0 ° C-5 ° C.

The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 84%. iv) Another 200 ml portion was concentrated to 3.5 g under reduced pressure. Then 3.5 ml of butyl acetate and 10.5 ml of acetonitrile were added. The resulting solution was then cooled to 0 ° C-5 °. The solution was then allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 83%. v) A 200 ml portion was concentrated to 3.5 g under reduced pressure. Then 3.5 ml of ethyl acetate were added and .5 ml of acetonitrile. Subsequently, 17.5 ml of isobutyl acetate were added. The resulting solution was then cooled to 0 ° C-5 ° C. The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 74%.

Example 2 Step to: Purification One kilogram of a fermentation broth containing pneumocandin B0 was combined with 0.5 liter of n-butyl acetate to form a two-phase system. The two phases were separated with a centrifuge. The n-butyl acetate phase was removed in such a manner that the pneumocandin B0 remained in the purified fermentation broth.

The purified fermentation broth was then extracted with 500 ml of n-butanol. The extraction was then repeated with another 500 ml of n-butanol. The two resulting n-butanol phases were combined to obtain an n-butanol phase of 1150 ml.

Step b: Crystallization The n-butanol phase was concentrated at 18 g under reduced pressure. Then 18 ml of isobutyl acetate and 54 ml of acetonitrile were added. The resulting solution was then cooled to 0 ° C-5 ° C.

The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 64%.

Example 3 Step to: Purification One kilogram of a fermentation broth containing pneumocandin Bo was combined with 0.5 liter of n-propyl acetate to form a two-phase system. The two phases were separated with a centrifuge. The n-propyl acetate phase was removed in such a manner that the pneumocandin B0 remained in the purified fermentation broth.

The purified fermentation broth was then extracted with 500 ml of isobutanol. The extraction was then repeated with another 500 ml of iso-butanol. The resulting two iso-butanol phases were combined to obtain an iso-butanol phase of 1140 ml.

Step b: Crystallization The isobutanol phase was concentrated to 9 g under reduced pressure. Then 9 ml of isobutyl acetate and 27 ml of acetonitrile were added. The resulting solution was then cooled to 0 ° C-5 ° C. The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 80%.

Example 4 Step to: Purification One kilogram of a fermentation broth containing pneumocandin Bo was combined with 0.5 liter of toluene to form a two-phase system. The two phases were separated with a centrifuge. The toluene phase was removed in such a manner that the pneumocandin B0 remained in the purified fermentation broth.

The purified fermentation broth was then extracted with 500 ml of isobutanol. The extraction was then repeated with another 500 ml of iso-butanol. The two resulting n-butanol phases were combined to obtain an iso-butanol phase of 1120 ml.

Step b: Crystallization The iso-butanol phase was concentrated to 12 g under reduced pressure. Then 12 ml of isobutyl acetate and 36 ml of acetonitrile were added. The resulting solution was then cooled to 0 ° C-5 ° C. The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 52%.

Example 5 Step to: Purification One kilogram of a fermentation broth containing pneumocandin Bo was combined with 0.5 liter of hexane acetate to form a two-phase system. The two phases were separated with a centrifuge. The hexane phase was removed in such a manner that the pneumocandin Bo remained in the purified fermentation broth.

The purified fermentation broth was then extracted with 500 ml of isobutanol. The extraction was then repeated with another 500 ml of iso-butanol. The two resulting n-butanol phases were combined to obtain an isobutanol phase of 910 ml.

Step b: Crystallization The isobutanol phase was concentrated at 18 g under reduced pressure. Then 18 ml of isobutyl acetate and 54 ml of acetonitrile were added. The resulting solution was then cooled to 0 ° C-5 ° C. The solution was allowed to stand for about 20 hours, during which crystallization occurred. The resulting crystals were then filtered from the solution and dried. The yield of the crude product was 88%.

Example 6 The fermented broth was filtered and the filtered mycelium was divided into several parts. Each part of the filtered mycelia was suspended in a solvent in a volume of 2 times the mass of the part of the filtered mycelium. After shaking, the mycelia were filtered from the solvent. Each solvent removed impurities. Solvents such as ethyl acetate, hexane, petroleum ether and dichloromethane resulted in the purification with a negligible loss. Solvents such as acetone, methanol, ethanol, n-propanol, isopropanol and acetonitrile resulted in the purification at a significant loss.

Example 7 Step to: 190 kg of fermented broth was extracted with pneumocandin, which contained 414.8 g of pneumocandin B0, with 95 L of iso-butanol at pH 5.0-7.0. The extraction step was repeated with another 95 L of isobutanol. The two resulting isobutanol phases were combined to obtain an isobutanol phase of 191 L.

The combined iso-butanol phase was evaporated to the volume of 25 L. This concentrate was washed twice with 12.5 L of water at pH 4.0-4.5. After acid washing the concentrate was washed twice with 6 L of water at pH 6.0-6.5.

The washed concentrate was rinsed with 193 g of activated carbon. After the carbon treatment the concentrate was evaporated to a volume of 4.8 L. 3.6 L of isobutyl acetate was added to a final concentrate and the solution was evaporated again to 4.8 L. This step was repeated .

The final concentrate obtained contained 296.7 g of pneumocandin Bo. The yield was 71.5%.

Step b: Precipitation of crude pneumocandin B0 to different carriers 1. 59.4 g of diatomaceous earth (the type used was FW-14) was added to a final concentrate of 250 ml volume. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of a mixture of acetonitrile-isobutyl acetate 1: 1. The filter cake was dried at 40 ° C for 12 hours. 87.2 g of crude product - containing 13.88 g of pneumocandin B0 - was prepared. The yield of precipitation was 89.9%. 2. 59.4 g corn flour was added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of a 1: 1 acetonitrile-ethyl acetate mixture. The filter cake was dried at 40 ° C for 12 hours. 77.09 g of crude product - containing 8.72 g of pneumocandin B0 - were prepared. The yield of precipitation was 56.5%. 59.4 g of corn starch were added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 80.02 g of the crude product - containing 12.63 g of pneumocandin B0 - were prepared. The yield of precipitation was 81.8%. 59.4 g of potato starch were added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 78.31 g of the crude product - containing 14.56 g of pneumocandin B0 - were prepared. The yield of precipitation was 94.3%. 59.4 g of bentonite (the type used was S-100) was added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 80.97 g of the crude product - containing 11.14 g of pneumocandin B0 - were prepared. The yield of precipitation was 72.2%. 59.4 g of bentonite (the type used was T2-350) were added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 81.14 g of the crude product - containing 10.70 g of pneumocandin B0 - were prepared. The yield of precipitation was 69.3%. 59.4 g of active carbon were added to a final concentrate of 500 ml volume. 800 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 1000 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 109.02 g of the crude product - containing 25.44 g of pneumocandin B0 - were prepared. The yield of precipitation was 82.4%. 19.8 g of perlite (the type used was CP-800) was added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 47.46 g of the crude product - containing 13.54 g of pneumocandin B0 - were prepared. The yield of precipitation was 87.7%. 59.4 g of Avicel (the type used was 200) were added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 81.65 g of the crude product - containing 9.62 g of pneumocandin Bo ~ were prepared. The yield of precipitation was 62.3%. 29.7 g of active lignite were added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 53.56 g of the crude product - containing 13.45 g of pneumocandin B0 - were prepared. The yield of precipitation was 87.1%. 19.8 g of hydrophobic perlite was added to a final 250 ml volume concentrate. 400 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 1 hour at room temperature. The mixture was filtered and the filter cake was suspended with 500 ml of acetonitrile-isobutyl acetate mixture 1: 1. The filter cake was dried at 40 ° C for 12 hours. 43.83 g of the crude product - containing 13.43 g of pneumocandin B0 - were prepared. The yield of precipitation was 86.9%.

Example 8 Step to 100.0 kg of fermented broth diluted with F-11899A, containing about 36.5 g of WF-11899A, was extracted with 100.0 L of iso-butanol at pH 5.0-7.0. The extraction step was repeated with an additional 60.0 L of iso-butanol. The resulting two iso-butanol phases were combined to obtain an iso-butanol phase of 161.0 L. The combined iso-butanol phase was evaporated to the volume of 12.3 L. This concentrate was washed twice with 6, 0 L of water at pH 4.0-4.5. After acid washing the concentrate was washed with 6.0 L of water at pH 6.0-6.5.

The washed concentrate was rinsed with 9.1 g of active carbon. After the carbon treatment the concentrate was divided into two parts. The first part (6.9 L) was evaporated to a volume of 1.3 L. An equal volume (1.3 L) of isobutyl acetate was added to the concentrate and the solution was evaporated again to the volume of the previous step. The step was repeated twice. The weight of the final concentrate was 740.41 g.

The second part (3.3 L) was evaporated to a weight of 337.3 g. A volume (300 ml) of isobutyl acetate was added to a concentrate and the solution was evaporated again to the volume of the previous step. This step was repeated twice. The weight of the second final concentrate was 316.07 g.

The final concentrate obtained contained 20.25 g of WF-11899A. The yield was 55.5%.

Step b: Precipitation of WF-11899A (FR-901379) raw to different carriers 1. 6.0 g of diatomaceous earth (the type used was FW-14) and 5.0 ml of isopropyl acetate were added to a final concentrate of 10 g of weight. 35 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 5 hours at room temperature. The mixture was filtered and the filter cake was suspended with 10 ml of acetonitrile. The filter cake was dried at 40 ° C for 12 hours. 10.0 g of the crude product - containing 213.1 mg of WF-11899A were prepared. The yield of precipitation was 98.6%. 2. 300.0 g of diatomaceous earth (the type used was FW-14) and 178.0 ml of isopropyl acetate were added to a final concentrate of 336.0 g of weight. 1176 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 5 hours at room temperature. The mixture was filtered and the filter cake was suspended with 336 ml of acetonitrile. The filter cake was dried at 40 ° C for 12 hours. 451.6 g of the crude product - containing 6.66 g of WF-11899A were prepared. The yield of precipitation was 91.7%. 6.0 g of perlite (the type used was CP-800) and 5.0 ml of isopropyl acetate were added to a final concentrate of 10 g of weight. 35 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 5 hours at room temperature. The mixture was filtered and the filter cake was suspended with 10 ml of acetonitrile. The filter cake was dried at 40 ° C for 12 hours. 9.61 g of the crude product - containing 221.3 mg of WF-11899A were prepared. The yield of precipitation was 98.3%. 6.0 g of Avicel (the type used was 200) and 5.0 ml of isopropyl acetate were added to a final concentrate of 10 g of weight. 35 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 5 hours at room temperature. The mixture was filtered and the filter cake was suspended with 10 ml of acetonitrile. The filter cake was dried at 40 ° C for 12 hours. 9.71 g of the crude product were prepared-containing 202.4 mg of F-11899A. The yield of precipitation was 93.6%.

. We added 400, 0 g of Avicel (the type used was 200) and 200.0 ml of isopropyl acetate to a final concentrate of 404.0 g. 1414 ml of acetonitrile was added to the suspension and the mixture was stirred for an additional 5 hours at room temperature. The mixture was filtered and the filter cake was suspended with 404 ml of acetonitrile. The filter cake was dried at 40 ° C for 12 hours. 549.2 g of the crude product - containing 8.31 g of WF-11899A were prepared. The yield of precipitation was 95.5%.

Example 9 Step to: The echinocandin-fermented broth is extracted with a volume of iso-butanol at pH 5.0-7.0. The extraction step was repeated with an additional volume of iso-butanol. The resulting two iso-butanol phases are combined.

The combined iso-butanol phase is concentrated and washed at acidic and neutral pH. The washed concentrate is rinsed with charcoal.

After the carbon treatment the concentrate is evaporated to an oily residue. Isobutyl acetate is added to the final concentrate and the solution is evaporated back to the initial volume. This step is repeated.

Step b: Precipitation of raw echinocandin Diatomaceous earth (the type used was FW-14) is added to the final concentrate. Acetonitrile is added to the suspension to precipitate the crude product. The mixture is stirred an additional hour at room temperature. The mixture is filtered and the filter cake is suspended with a mixture of acetonitrile: isobutyl acetate 1: 1. The filter cake is dried at 40 ° C for 12 hours.

Example 10: Separation of the active substance, pneumocandin B0, from the carrier Ten kilograms of the pneumocandin B0 crude product (on diatomaceous earth, assay: 13.07%, HPLC purity: 35.7%) containing 1307 g of the active substance was stirred with 100 L of normal propanol for 1 hour. The diatomaceous earth was filtered and washed with 10 L of normal propanol. The combined propanolic solution (approximately 110 L) was evaporated under reduced pressure to a volume of 11.4 L. 46 L of isopropyl acetate was added to the concentrate and the mixture was cooled to (-) 10 ° C - (-) 20 ° C. The mixture was stirred for another 16-18 hours at (-) 10 ° C - (-) 20 ° C. The precipitated material was filtered and washed with 10 L of isopropyl acetate. The pneumocandin B0 was dried at 40 ° C for about 12 hours. The mass of the product was 4.89 kg. The test was 26.21% and the purity of HPLC was 41.12. The yield of the step was 98%.

Claims (67)

1. A process for purifying an echinocandin-type compound comprising: (a) extracting impurities from a whole broth having an echinocandin-like compound with at least one organic solvent immiscible with non-polar or weakly polar water to obtain a first system of two phases comprising an aqueous phase and an organic phase; (b) removing the organic phase to obtain the aqueous phase; (c) extracting the echinocandin-like compound from the aqueous phase with an organic solvent immiscible with water to obtain a second two-phase system; and (d) removing the purified echinocandin-type compound, wherein the water-immiscible organic solvents of steps (a) and (c) are different.

2. The process according to claim 1, wherein the echinocandin-type compound is selected from the group consisting of pneumocandin B0, F-11899 and echinocandin.

3. The process according to claim 1 or 2, wherein the echinocandin type compound is present in the whole broth at a concentration of 0.2 to 15 g / L.

4. The process according to any of the preceding claims, wherein the organic solvent immiscible with non-polar or weakly polar water is selected from the group consisting of aliphatic alkanes of C5_8, aromatic hydrocarbons of ^ -Q, ethers of 04_8 and esters of C3_6.

5. The according to claim 4, wherein the organic solvent immiscible with non-polar or weakly polar water is heptane, hexane, octane, cyclohexane, toluene, diethyl ether, diisopropyl ether, dibutyl ether, iso-butyl acetate, n-acetate. -butyl, n-propyl acetate, isopropyl acetate and ethyl acetate.

6. The process according to claim 5, wherein the organic solvent immiscible with non-polar or weakly polar water is iso-butyl acetate, n-butyl acetate, n-propyl acetate, isopropyl acetate or ethyl acetate.

7. The process according to any of the preceding claims, wherein the amount of the organic solvent immiscible with non-polar or weakly polar water in the first phase system is from 5% to 90% by volume of the whole broth.

8. The process according to claim 7, wherein the amount of the organic solvent immiscible with non-polar or weakly polar water is 50% to 90% by volume of the whole broth.

9. The process according to claim 7, wherein the amount of the organic solvent immiscible with non-polar or weakly polar water is from 10% to 50% by volume of the whole broth.

10. The process according to claim 9, wherein the amount of the organic solvent immiscible with non-polar or weakly polar water is 30% to 50% by volume of the whole broth.

11. The process according to any one of the preceding claims, wherein the organic solvent immiscible with water of step (c) is an alcohol immiscible with water.

12. The process according to claim 11, wherein the alcohol immiscible with water is a C 4-6 alcohol

13. The process according to claim 12, wherein the C 4-6 alcohol is isobutanol or n-butanol.

14. The process according to any of the preceding claims, wherein the extraction of step (c) is repeated.

15. The process according to any of the preceding claims, which also comprises the step of crystallizing the echinocandin-type compound, preferably by a process comprising mixing the recovered echinocandin-like compound with at least one antisolvent.

16. The process according to claim 15, wherein the antisolvent is selected from the group consisting of ethyl acetate, isobutyl acetate, n-butyl acetate, tere-butyl acetate, isopropyl acetate, acetone, acetonitrile (ACN), mixtures of acetonitrile with ethyl acetate and mixtures of acetonitrile (ACN) and isobutyl acetate.

17. The process according to claim 16, wherein the antisolvent is acetonitrile.

18. The process according to claim 16, wherein the antisolvent is ethyl acetate or isobutyl acetate and the precipitation is induced by a cooling step or by the addition of a second antisolvent.

19. The process according to claim 18, wherein the cooling step is at a temperature of 5 ° C to -20 ° C.

20. The process according to claim 19, wherein the cooling is at a temperature of 5 ° C to 0 ° C.

21. The process according to claim 18, wherein the second antisolvent is acetone or acetonitrile.

22. The process according to claim 21, wherein the second antisolvent is acetonitrile or acetone and the precipitation is induced by cooling to a temperature of 5 ° C to -20 ° C.

23. The process according to any of claims 15 to 22, which also comprises cooling the mixture of the echinocandin-type compound and the antisolvent at a temperature of 5 ° C to -20 ° C for a period of at least 15 minutes.

24. The process according to claim 23, wherein the cooling is at a temperature of 5 ° C to 0 ° C.

25. The process according to claim 23 or 24, wherein the period is from 10 hours to 24 hours.

26. The process according to claim 25, wherein the period is 20 hours.

27. A process for purifying an echinocandin-type compound comprising crystallizing an echinocandin-type compound using at least one antisolvent.

28. The process according to claim 27, wherein the initial echinocandin-type compound is obtained from the extractions of the fermentation broth.

29. The process according to claim 27, wherein the antisolvent is selected from the group consisting of ethyl acetate, isobutyl acetate, n-butyl acetate, tere-butyl acetate, isopropyl acetate, acetone, acetonitrile (ACN), mixtures of acetonitrile with ethyl acetate and mixtures of acetonitrile (ACN) and isobutyl acetate.

30. The process according to claim 29, wherein the antisolvent is acetonitrile.

31. The process according to claim 29, wherein the antisolvent is ethyl acetate or isobutyl acetate and the precipitation is induced by a cooling step or by the addition of a second antisolvent.

32. The process according to claim 31, wherein the cooling step is at a temperature of 5 ° C to -20 ° C.

33. The process according to claim 32, wherein the cooling is at a temperature of 5 ° C to 0 ° C.

34. The process according to claim 31, wherein the second antisolvent is acetone or acetonitrile.

35. The process according to claim 34, wherein the second antisolvent is acetonitrile or acetone and the precipitation is induced by cooling to a temperature of 5 ° C to -20 ° C.

36. The process according to any of claims 27 to 35, which also comprises cooling the mixture of the echinocandin-type compound recovered and the antisolvent at a temperature of 5 ° C to -20 ° C for a period of at least 15 minutes. .

37. The process according to claim 36, wherein the cooling is at a temperature of 5 ° C to 0 ° C.

38. The process according to claim 36 or 37, wherein the period is from 10 hours to 24 hours.

39. The process according to claim 38, wherein the period is 20 hours.

40. The process according to any of the preceding claims, which also comprises converting the purified echinocandin-like compound into caspofungin, anidulafungin or micafungin.

41. A process for purifying an echinocandin-type compound comprising: (a) extracting the echinocandin-like compound from a fermentation broth or from a filtered mycelium obtained from a fermentation broth, with an organic solvent immiscible with water to obtain a a two-phase system comprising an aqueous phase and an organic phase or to obtain an organic phase containing water; (b) recovering the echinocandin type compound; and (c) combining the echinocandin-type compound recovered with at least one antisolvent and a solid carrier to obtain a purified echinocandin-like compound.

42. The process according to claim 41, wherein the organic solvent immiscible with water of step (a) is an alcohol immiscible with water.

43. The process according to claim 42, wherein the alcohol immiscible with water is a C 4-6 alcohol.

44. The process according to claim 43, wherein the C 4-6 alcohol is isobutanol or n-butanol.

45. The process according to any of claims 41 to 44, wherein the extraction of step (a) is carried out at a pH of 2 to 8.

46. The process according to claim 45, wherein the pH is from 5 to 7.

47. The process according to claim 45, wherein the pH is from 2 to 4 and the extraction is carried out while cooling to a temperature below 10 ° C.

48. The process according to claim 47, wherein the cooling is at a temperature of 0 ° C to 10 ° C.

49. The process according to any of claims 41 to 48, wherein the extraction step (a) is repeated.

50. The process according to any of claims 41 to 49, which also comprises a washing step of the echinocandin-like compound, before combining the echinocandin-like compound with recovered with an antisolvent and a solid carrier in step c) .

51. The process according to claim 50, wherein the washing step comprises combining the echinocandin-type compound with water.

52. The process according to claim 51, wherein the washing step comprises two steps, one using water having a pH of from 4 to 6.5, and one second, using water having a pH of from 4 to 6.5.

53. The process according to claim 52, wherein the first washing with water has a pH of 4 to 4.5 and the second washing with water has a pH of 6 to 6.5.

54. The process according to any of claims 50 to 53, wherein the wash removes from 20% to 50% by weight of solid waste originating in the fermentation broth.

55. The process according to any of claims 41 to 54, which also comprises a step of treating the echinocandin-like compound with active carbon before combining the echinocandin-like compound recovered with an antisolvent and a solid carrier as in step (c).

56. The process according to any of claims 41 to 55, which also comprises the step of crystallizing the echinocandin-type compound comprising combining it with at least one antisolvent and a solid carrier to obtain a compound of the echinocandin-purified type.

57. The process according to any of claims 41 to 56, wherein the solid carrier is selected from the group consisting of active carbon, diatomaceous earth, wheat flour, corn starch, potato starch, bentonite, perlite, avicel, hydrophobic perlite , active lignite flours, carbons and cellulose products.

58. The process according to any of claims 41 to 57, wherein the antisolvent is selected from the group consisting of ethyl acetate, isobutyl acetate, n-butyl acetate, tere-butyl acetate, isopropyl acetate, acetone, acetonitrile (ACN), mixtures of acetonitrile with ethyl acetate and mixtures of acetonitrile (ACN) with iso-butyl acetate.

59. The process according to any of claims 41 to 58, wherein the recovery of the echinocandin-like compound comprises filtering the mixture of the echinocandin-like compound, the solid carrier and the antisolvent and suspending the filtered solid carrier to which it is absorbed. the echinocandin-type compound in a solvent selected from the group consisting of acetonitrile, acetone or a mixture of two organic solvents.

60. The process according to claim 59, wherein the mixture of two organic solvents comprises a first solvent selected from the group consisting of isobutyl acetate, isopropyl acetate, ethyl acetate, octane and a second solvent selected from the group consisting of acetonitrile or acetone.

61. The process according to any of claims 41 to 60, wherein the echinocandin-type compound is separated from the solid carrier comprising the step of combining the solid carrier to which the echinocandin compound is absorbed with a solvent in which the Echinocandin type compound is soluble.

62. The process according to claim 61, wherein the solvent in which the echinocandin-type compound is soluble is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), a mixture of them and a mixture of them in water.

63. A process for purifying an echinocandin-type compound comprising combining an echinocandin-like compound with at least one antisolvent and a solid carrier.

64. The process according to claim 63, wherein the initial echinocandin-type compound is obtained from extractions of the fermentation broth.

65. The process according to any of claims 41 to 64, which also comprises the step of converting the echinocandin type compound. purified is caspofungin, anidulafungin or micafungin.

66. The use of a process according to any of the preceding claims in the manufacture of an echinocandin fungicide.

67. The use according to claim 66, wherein the echinocandin fungicide caspofungin, micafungin and anidulafungin.