WO2010064219A1 - Process for the preparation of a novel intermediate for caspofungin - Google Patents
Process for the preparation of a novel intermediate for caspofungin Download PDFInfo
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- WO2010064219A1 WO2010064219A1 PCT/IB2009/055526 IB2009055526W WO2010064219A1 WO 2010064219 A1 WO2010064219 A1 WO 2010064219A1 IB 2009055526 W IB2009055526 W IB 2009055526W WO 2010064219 A1 WO2010064219 A1 WO 2010064219A1
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- 0 **(**1)c2c1cccc2 Chemical compound **(**1)c2c1cccc2 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
Definitions
- the present invention provides a process for preparing a novel intermediate of Formula IV,
- antifungal agent such as caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
- Echinocandins and echinocandin-like cyclohexapeptide compounds are described in literature as highly effective antifungal agents, particularly against yeast causing myotic infections such as Candida albicans, Candida parapsilosis, and the like.
- Some of these compounds are natural products produced by the cultivation of microorganisms, such as Aspergillus rugulosus, Aspergillus nidulans and Acrophialophoria lemonispora described in U.S. Patent Nos. 4,024,245; 4,024,246; and 4,173,629 respectively.
- Some of these compounds are semisynthetic and can be produced by modifying the natural products as described in U.S. Patent Nos. 4,293,489; 4,320,053; 4,370,054; 4,322,338; 5,378,804; 5,965,525; and 5,376,634.
- Cancidas® (caspofungin acetate), l-[(4R,5S)-5-[(2-aminoethyl)amino]-N 2 -(10,12- dimethyl-loxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin Bo diacetate (salt), is the first of a new class of antifungal drugs (echinocandins) that inhibit the synthesis of ⁇ (l,3)-D-glucan, an integral component of the fungal cell wall.
- echinocandins antifungal drugs
- Candida infections like: intra-abdominal abscesses, peritonitis and pleural space infections. It is also indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid Formulations of amphotericin B, and/or itraconazole). It is further indicated for the treatment of esophageal candidiasis.
- U.S. Patent No. 5,378,804 discloses the reaction of pneumocandin B 0 with 2- aminoethanethiol in the presence of an acid, followed by oxidation to give sulfone which is made to react with ethylene diamine to give caspofungin in low yields; resulting from the lack of stereoselectivity and chemoselectivity of the process.
- U.S. Patent No. 5,552,521 describes the process for the preparation of caspofungin involving the reduction of the pneumocandin Bo followed by the reaction with thiophenol and displacement of phenyl-thio group with ethylene diamine.
- U.S. Patent No. 5,936,062 describes the process involving the reaction of pneumocandin B 0 with boronic acid, followed by reduction and then reaction with thiophenol, which upon displacement with ethylene diamine, provides caspofungin.
- the present invention provides a process for preparing a novel intermediate which can be effectively used for the preparation of antifungal agents such as caspofungin, derivatives, and pharmaceutically acceptable salt thereof.
- the present invention provides a process for preparing a novel intermediate of Formula IV,
- Ri is hydrogen, Ci -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy;
- R 2 is Ci_C 2 o alkyl, C 1 -C 2 0 alkoxy, C 2 -C 2 0 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Ci 0 alkyl, Ci-Ci 0 alkoxy, aryl or Cs-Coheteroaryl, which can be effectively used for the preparation of antifungal agents.
- the invention further provides a process for preparing caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
- One aspect of the present invention provides a process for preparing a novel intermediate of Formula IV,
- R x is hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy, C 1 -C 4 alkoxy
- R 2 is Ci-C 20 alkyl, Ci-C 20 alkoxy, C 2 -C 20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Ci 0 alkyl, Ci-Ci 0 alkoxy, aryl or Cs-Ceheteroaryl,
- the process comprises the steps of: a) converting a compound of Formula I
- R2 is C1-C20 alkyl, C1-C20 alkoxy, C2- C 20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, aryl or C5-C6 heteroaryl.
- the process comprises the steps of: a) reacting a compound of Formula I with cyanuric chloride
- the present invention provides a novel intermediate of Formula IV,
- Ri is hydrogen, Ci -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy
- R 2 is Ci C 2 0 alkyl, C 1 -C 2 0 alkoxy, C 2 -C 2 0 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, ammo, hydroxyl, Q-Cio alkyl, Ci-Ci 0 alkoxy, aryl or Cs-Cgheteroaryl.
- a pharmaceutical composition comprising: a) a compound of Formula V
- R 2 is -(CH 2 )SCH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ); and b) one or more compound selected from
- the compounds in component b) are present in an amount up to 2% (suitably up to 0.2%), based upon 100% total weight of components a) and b).
- the compound in component a), i.e., the active ingredient is preferably present in an amount greater than 95% and more preferably greater than 98% or 99% based upon 100% total weight of component a) and b).
- alkyl refers to a straight or branched chain alkyl group optionally substituted with 1-3 halogen, C 1 -C 5 alkoxy, hydroxy or amino.
- Representative examples include C 1 -C 2 0 alkyl such as methyl, ethyl, propyl, butyl or - (CH 2 )SCH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ).
- alkoxy includes straight or branched alkyl as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples include methoxy or ethoxy.
- alkenyl includes straight or branched alkyl group as defined above having unsaturation.
- aryl includes aromatic radicals having in the range of 6 to 14 carbon atoms such as phenyl, napthyl, biphenyl, and the like.
- heteroaryl includes saturated or unsaturated 5 or 6 membered cyclic radical where-in one or two carbon atoms in the ring may be replaced by N or O; which may be optionally substituted with C 1 -C 1 0 alkyl, C 1 -C 1 0 alkoxy, halogen or amino.
- halogen includes fluorine, chlorine, bromine or iodine.
- room temperature means a temperature range of about 25° C to about 30 0 C.
- pharmaceutically acceptable salts includes the acid addition salts of inorganic acids, (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like), or organic acids, (e.g., acetic acid, trifluoroacetic acid fumaric acid, citric acid, succinic acid, tartaric acid, maleic acid, oxalic acid, malic acid, glutamic acid, or the like).
- inorganic acids e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like
- organic acids e.g., acetic acid, trifluoroacetic acid fumaric acid, citric acid, succinic acid, tartaric acid, maleic acid, oxalic acid, malic acid, glutamic acid, or the like.
- the present invention provides a process for preparing a novel intermediate of
- Ri is hydrogen, Ci -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy
- R 2 is Ci-C 2 O alkyl, Ci-C 2 O alkoxy, C 2 -C 2 O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl.
- the process comprises the steps of: a) converting a compound of Formula I
- the step a) involves converting a compound of Formula I to a compound of Formula III, wherein the conversion can be effected by dehydrating the compound of Formula I to give a compound of Formula II, which upon reduction gives a compound of Formula III.
- the dehydrating agent used in step a) can be selected from anhydrides (e.g., acetic anhydride or trifluoroacetic anhydride); acid chlorides (e.g., cyanuric chloride, oxalyl chloride, phosphorus oxychloride, thionyl chloride, p- toluenesulfonyl chloride or chlorosulfonyl isocyanate); phosphonium reagents (e.g., phosphorus pentaoxide, phosphorus pentachloride, triphenylphosphine/carbon tetrachloride, triphenylphosphonium ditriflate or triphenylphosphonium dichloride); carbodiimides (e.g., dicyclohexylcarbodiimide or the like) or other dehydrating agents (e.g., aluminum chloride, titanium tetrachloride or ethyl(carboxysulfamoyl
- Suitable solvents used in the dehydration step may include from polar aprotic solvents (e.g., dimethylformamide, dimethylsulf oxide, N-methylpyrrolidine or dime thy lacetamide), weakly basic solvents (e.g., pyridine, collidine or the like).
- the reducing agent used in this step may include metal hydrides (e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, lithium aluminum hydride, diborane, diisobutyl aluminum hydride or the like), catalytic reducing agents (e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like).
- Step a) may also be carried out by reducing a compound of Formula I directly to a compound of Formula III, wherein the reducing agents may include borane complex (e.g., borane in tetrahydrofuran, dimethylsulfide, diphenylsulfide, dibenzylsulfide, 1 ,4-oxathiane or chloroborohydride in dimethylsulfide), metal boride (sodium borohydride with zirconium chloride or titanium chloride, titanium or zirconium borides), or as exemplified in U.S. Patent Nos. 5,348,940; 5,378,804, or 6,030,944.
- borane complex e.g., borane in tetrahydrofuran, dimethylsulfide, diphenylsulfide, dibenzylsulfide, 1 ,4-oxathiane or chloroborohydride in dimethylsulfide
- metal boride
- Step b) can be carried out in presence of an acid in a polar aprotic solvent to give a compound of Formula IV.
- the acid may be organic acids (e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid), or a mixture thereof.
- organic acids e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid
- inorganic acids e.g., hydrochloric acid, sulfuric acid or phospho
- the polar aprotic solvent may include dimethylformamide, dimethylsulf oxide, acetate (e.g., ethyl acetate or the like), nitriles (e.g., acetonitrile, propionitrile, or the like), ketones (e.g., acetone, diethylketone, methylethylketone or the like) or a mixture thereof.
- a compound of Formula I may be treated with acid chloride such as cyanuric chloride, oxalyl chloride, phosphorus oxychloride or thionyl chloride, suitably cyanuric chloride in dimethylformamide at low temperature to give a compound of Formula II.
- the compound of Formula II may be reduced using any reducing agent known to a person of ordinary skill in the art including for example, sodium borohydride in the presence of nickel chloride hexahydrate.
- the compound of Formula III is reacted with a compound of Formula VI, (e.g., 1-hydroxybenzotriazole) in the presence of triflouroacetic acid in acetonitrile to give an intermediate of Formula IV.
- a compound of Formula VI e.g., 1-hydroxybenzotriazole
- the intermediate of Formula IV may be prepared by reacting a compound of Formula I with a compound of Formula VI to give a compound of Formula Ha,
- the intermediate of Formula IV may be prepared by dehydrating a compound of Formula I to give a compound of Formula II, which upon reaction with a compound of Formula VI, gives a compound of Formula Ilia.
- the above process further comprises converting an intermediate of Formula IV to a compound of Formula V (e.g., caspofungm), or pharmaceutically acceptable salts thereof.
- a compound of Formula V e.g., caspofungm
- Ri is hydrogen and R 2 is Ci-C 20 alkyl group, preferably -(CH 2 ) S CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ).
- the present invention also provides a process for preparing a compound of Formula V,
- R 2 is Ci C 2 o alkyl, Ci-C 2O alkoxy, C 2 -C 2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, ammo, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl.
- the process comprises the steps of: a) reacting a compound of Formula I with cyanuric chloride
- step a) may be carried out in a solvent including a polar aprotic solvent (e.g., dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine or dimethylacetamide), weakly basic solvent (e.g., pyridine, collidine or the like), or a mixture thereof.
- a polar aprotic solvent e.g., dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine or dimethylacetamide
- weakly basic solvent e.g., pyridine, collidine or the like
- Step b) may be carried out in presence of one or more reducing agents including metal hydrides (e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, aluminum hydride, diborane, diisobutyl aluminum hydride or the like), catalytic reducing agents (e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like), or a mixture thereof.
- metal hydrides e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, aluminum hydride, diborane, diisobutyl aluminum hydride or the like
- catalytic reducing agents e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like
- Step c) may be carried out in the presence of an acid in a polar aprotic solvent.
- the acid may include organic acids (e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid), or mixtures thereof.
- organic acids e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid
- inorganic acids e.g., hydrochloric acid, sulfuric acid or phosphoric acid
- the polar aprotic solvent may include dimethylformamide, dimethylsulfoxide, acetate (e.g., ethyl acetate or the like), nitriles (e.g., acetonitrile, propionitrile or the like), ketones (e.g., acetone, diethylketone, methylethylketone or the like), or mixtures thereof.
- Step d) involves reacting a compound of Formula IV with ethylene diamine and optionally converting the compound of Formula V (wherein Ri is hydrogen, R 2
- the present invention further provides a compound having the structure of
- Ri is hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy
- R 2 is Ci_C 2 o alkyl, Ci-C 2 O alkoxy, C 2 -C 2 O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Ci 0 alkoxy, aryl or C5-C6 heteroaryl.
- R x is hydrogen and R 2 is Ci- C 20 alkyl group, preferably -(CH 2 )8CH(CH3)CH 2 CH(CH3)CH 2 CH3).
- Example 1 Preparation of a Compound of Formula II (wherein R 2 is - (CH 2 )RCH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 )
- Cyanuric chloride (3.11 g; 16.90 mmole) was added to a solution of Pneumocandin B 0 (20 g, 18.78 mmole) in dry dimethylformamide (200 mL; water content below 0.10% (w/w)) at about -30° C for about 20 hours. After the completion of reaction, water (200 mL) was added over 15 minutes and the mixture was warmed to room temperature. The above mixture was slowly poured into vigorously stirred water (2400 mL) at ambient temperature. The suspension was stirred for about 2 hours and filtered.
- reaction mixture was poured into ortho phosphoric acid solution in water (7%; 373 mL) at about 0° C.
- tetrahydrofuran 200 mL
- the above suspension was stirred at about 0° C to 5° C for 3 to 4 hours.
- the above solution was saturated with sodium chloride (55 g).
- the organic layer was separated and mixed with water (300 mL) at a temperature range of about 5° C to 10° C.
- the pH of the mixture was adjusted to about 6.5 using sodium bicarbonate solution in water (5%; 140 mL).
- the above suspension was stirred at a temperature range of about 5° C to 10° C for about 1 hour.
- the solid was isolated by filtration further washed with acetonitrile (50 mL) and dried at room temperature.
- the pH of the above suspension was adjusted to about 6.5 using saturated dipotassium hydrogen phosphate (K 2 HP ⁇ 4 ; 100 mL) at 0° C. After decanting the upper clear solution, sticky solid thus obtained was stirred with water (50 ml) at room temperature for 1 hour and the solid was filtered. The solid was collected and dried at room temperature.
- K 2 HP ⁇ 4 saturated dipotassium hydrogen phosphate
- the above solid was purified by reverse phase chromatography using the acetonitrile and orthophosphoric acid (0.1% in water) as eluent in the ratio 20:80.
- the rich cuts were combined and concentrated to provide 0.5 g of compound of Formula V with 97% HPLC purity.
- the above solid can be purified by reverse phase chromatography using acetonitrile and acetic acid (0.1% in water) as eluent in the ratio 20:80.
- Example 4 The compound of Formula V (Example 4; 0.20 g) was dissolved in ethanol (2.30 mL) and water (0.20 mL) at room temperature. To this solution was added acetic acid (0.012 mL) at about 10° C followed by slow addition (1 hour) of ethyl acetate (5.0 mL). After stirring at room temperature for 30 minutes, the solid was filtered under inert atmosphere to get caspofungin diacetate.
Abstract
The present invention provides a process for preparing a novel intermediate of Formula (IV) which can be effectively used for the preparation of antifungal agent such as caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
Description
PROCESS FOR THE PREPARATION OF A NOVEL INTERMEDIATE FOR
CASPOFUNGIN
Field of the Invention
The present invention provides a process for preparing a novel intermediate of Formula IV,
which can be effectively used for the preparation of antifungal agent such as caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
Background of the Invention Echinocandins and echinocandin-like cyclohexapeptide compounds are described in literature as highly effective antifungal agents, particularly against yeast causing myotic infections such as Candida albicans, Candida parapsilosis, and the like. Some of these compounds are natural products produced by the cultivation of microorganisms, such as Aspergillus rugulosus, Aspergillus nidulans and Acrophialophoria lemonispora described in U.S. Patent Nos. 4,024,245; 4,024,246; and 4,173,629 respectively. Some of these compounds are semisynthetic and can be produced by modifying the natural products as described in U.S. Patent Nos. 4,293,489; 4,320,053; 4,370,054; 4,322,338; 5,378,804; 5,965,525; and 5,376,634.
Cancidas® (caspofungin acetate), l-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12- dimethyl-loxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin Bo diacetate (salt), is the first of a new class of antifungal drugs (echinocandins) that inhibit the synthesis of β(l,3)-D-glucan, an integral component of the fungal cell wall. It is indicated in adults and pediatric patients for empirical therapy for presumed fungal infections in febrile, neutropenic patients and used for treatment of
candidemia, and the following Candida infections like: intra-abdominal abscesses, peritonitis and pleural space infections. It is also indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid Formulations of amphotericin B, and/or itraconazole). It is further indicated for the treatment of esophageal candidiasis.
Several processes have been reported for the preparation of caspofungin, its derivatives, and pharmaceutically acceptable salts.
U.S. Patent No. 5,378,804 discloses the reaction of pneumocandin B0 with 2- aminoethanethiol in the presence of an acid, followed by oxidation to give sulfone which is made to react with ethylene diamine to give caspofungin in low yields; resulting from the lack of stereoselectivity and chemoselectivity of the process.
U.S. Patent No. 5,552,521 describes the process for the preparation of caspofungin involving the reduction of the pneumocandin Bo followed by the reaction with thiophenol and displacement of phenyl-thio group with ethylene diamine. U.S. Patent No. 5,936,062 describes the process involving the reaction of pneumocandin B0 with boronic acid, followed by reduction and then reaction with thiophenol, which upon displacement with ethylene diamine, provides caspofungin.
An improved method directed to the minimization of the epimerization of benzylic position and enhancing the α/β stereo selectivity of the product is described in U.S. Patent No. 7,214,768, this involves the reaction of pneumocandin with boronic acid, dehydrating the resulting borate with cyanuric chloride followed by reduction of the nitrile and reaction with phenylsulfide and finally displacement of the phenyl-thio group with the ethylene diamine to yield caspofungin. All the processes described above are not significantly stereoselective and/or high yielding. Taking into account the drawbacks of the aforementioned methods, the present invention provides a process for preparing a novel intermediate which can be effectively used for the preparation of antifungal agents such as caspofungin, derivatives, and pharmaceutically acceptable salt thereof.
Summary of the Invention
The present invention provides a process for preparing a novel intermediate of Formula IV,
R2 is Ci_C2o alkyl, C1-C20 alkoxy, C2-C20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Ci0 alkyl, Ci-Ci0 alkoxy, aryl or Cs-Coheteroaryl, which can be effectively used for the preparation of antifungal agents. The invention further provides a process for preparing caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
One aspect of the present invention provides a process for preparing a novel intermediate of Formula IV,
pharmaceutically acceptable salts thereof, wherein Rx is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, C1-C4 alkoxy; R2 is Ci-C20 alkyl, Ci-C20 alkoxy, C2-C20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Ci0 alkyl, Ci-Ci0 alkoxy, aryl or Cs-Ceheteroaryl,
The process comprises the steps of: a) converting a compound of Formula I
Formula VI to give a compound of Formula IV, wherein Ri and R2 are as defined above. Another aspect of the present invention provides a process for preparing a compound of Formula V,
pharmaceutically acceptable salts thereof, wherein R2 is C1-C20 alkyl, C1-C20 alkoxy, C2- C20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, aryl or C5-C6 heteroaryl.
The process comprises the steps of: a) reacting a compound of Formula I with cyanuric chloride
R LT\
Formula VI
to give a compound of Formula IV;
d) converting a compound of Formula IV to a compound of Formula V or pharmaceutically acceptable salts thereof.
According to another aspect, the present invention provides a novel intermediate of Formula IV,
pharmaceutically acceptable salts thereof, wherein Ri is hydrogen, Ci -C4 alkyl, halogen, nitro, hydroxy, Ci-C4 alkoxy; R2 is Ci C20 alkyl, C1-C20 alkoxy, C2-C20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, ammo, hydroxyl, Q-Cio alkyl, Ci-Ci0 alkoxy, aryl or Cs-Cgheteroaryl.
According to yet another aspect of the present invention, there is provided a pharmaceutical composition comprising: a) a compound of Formula V
and/or a pharmaceutically acceptable salt thereof wherein R2 is -(CH2)SCH(CH3)CH2CH(CH3)CH2CH3); and b) one or more compound selected from
According to a preferred embodiment, the compounds in component b) are present in an amount up to 2% (suitably up to 0.2%), based upon 100% total weight of components a) and b). The compound in component a), i.e., the active ingredient is preferably present in an amount greater than 95% and more preferably greater than 98% or 99% based upon 100% total weight of component a) and b).
Detailed Description of the Invention The following definitions apply to terms, as used herein:
The term "alkyl" refers to a straight or branched chain alkyl group optionally substituted with 1-3 halogen, C1-C5 alkoxy, hydroxy or amino. Representative examples
include C1-C20 alkyl such as methyl, ethyl, propyl, butyl or - (CH2)SCH(CH3)CH2CH(CH3)CH2CH3).
The term "alkoxy" includes straight or branched alkyl as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples include methoxy or ethoxy.
The term "alkenyl" includes straight or branched alkyl group as defined above having unsaturation.
The term "aryl" includes aromatic radicals having in the range of 6 to 14 carbon atoms such as phenyl, napthyl, biphenyl, and the like. The term "heteroaryl" includes saturated or unsaturated 5 or 6 membered cyclic radical where-in one or two carbon atoms in the ring may be replaced by N or O; which may be optionally substituted with C1-C10 alkyl, C1-C10 alkoxy, halogen or amino.
The term "halogen" includes fluorine, chlorine, bromine or iodine.
The term "room temperature" means a temperature range of about 25° C to about 300 C.
The term "pharmaceutically acceptable salts" includes the acid addition salts of inorganic acids, (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like), or organic acids, (e.g., acetic acid, trifluoroacetic acid fumaric acid, citric acid, succinic acid, tartaric acid, maleic acid, oxalic acid, malic acid, glutamic acid, or the like). The present invention provides a process for preparing a novel intermediate of
Formula IV,
pharmaceutically acceptable salts thereof, wherein Ri is hydrogen, Ci -C4 alkyl, halogen, nitro, hydroxy, Ci-C4 alkoxy; R2 is Ci-C2O alkyl, Ci-C2O alkoxy, C2-C2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl.
The process comprises the steps of: a) converting a compound of Formula I
Formula VI to give a compound of Formula IV, wherein Rx and R2 are same as defined above. In the above process, the step a) involves converting a compound of Formula I to a compound of Formula III, wherein the conversion can be effected by dehydrating the compound of Formula I to give a compound of Formula II, which upon reduction gives a compound of Formula III. The dehydrating agent used in step a) can be selected from
anhydrides (e.g., acetic anhydride or trifluoroacetic anhydride); acid chlorides (e.g., cyanuric chloride, oxalyl chloride, phosphorus oxychloride, thionyl chloride, p- toluenesulfonyl chloride or chlorosulfonyl isocyanate); phosphonium reagents (e.g., phosphorus pentaoxide, phosphorus pentachloride, triphenylphosphine/carbon tetrachloride, triphenylphosphonium ditriflate or triphenylphosphonium dichloride); carbodiimides (e.g., dicyclohexylcarbodiimide or the like) or other dehydrating agents (e.g., aluminum chloride, titanium tetrachloride or ethyl(carboxysulfamoyl)triethylammonium hydroxide inner salt). Suitable solvents used in the dehydration step may include from polar aprotic solvents (e.g., dimethylformamide, dimethylsulf oxide, N-methylpyrrolidine or dime thy lacetamide), weakly basic solvents (e.g., pyridine, collidine or the like). The reducing agent used in this step may include metal hydrides (e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, lithium aluminum hydride, diborane, diisobutyl aluminum hydride or the like), catalytic reducing agents (e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like). Step a) may also be carried out by reducing a compound of Formula I directly to a compound of Formula III, wherein the reducing agents may include borane complex (e.g., borane in tetrahydrofuran, dimethylsulfide, diphenylsulfide, dibenzylsulfide, 1 ,4-oxathiane or chloroborohydride in dimethylsulfide), metal boride (sodium borohydride with zirconium chloride or titanium chloride, titanium or zirconium borides), or as exemplified in U.S. Patent Nos. 5,348,940; 5,378,804, or 6,030,944.
Step b) can be carried out in presence of an acid in a polar aprotic solvent to give a compound of Formula IV. The acid may be organic acids (e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid), or a mixture thereof. The polar aprotic solvent may include dimethylformamide, dimethylsulf oxide, acetate (e.g., ethyl acetate or the like), nitriles (e.g., acetonitrile, propionitrile, or the like), ketones (e.g., acetone, diethylketone, methylethylketone or the like) or a mixture thereof. In one embodiment of the present invention, a compound of Formula I may be treated with acid chloride such as cyanuric chloride, oxalyl chloride, phosphorus
oxychloride or thionyl chloride, suitably cyanuric chloride in dimethylformamide at low temperature to give a compound of Formula II. In another embodiment, the compound of Formula II may be reduced using any reducing agent known to a person of ordinary skill in the art including for example, sodium borohydride in the presence of nickel chloride hexahydrate. In yet another embodiment, the compound of Formula III is reacted with a compound of Formula VI, (e.g., 1-hydroxybenzotriazole) in the presence of triflouroacetic acid in acetonitrile to give an intermediate of Formula IV.
According to one embodiment, the intermediate of Formula IV may be prepared by reacting a compound of Formula I with a compound of Formula VI to give a compound of Formula Ha,
which upon either reduction or dehydration, followed by a reduction, gives the intermediate of Formula IV.
According to another embodiment, the intermediate of Formula IV may be prepared by dehydrating a compound of Formula I to give a compound of Formula II, which upon reaction with a compound of Formula VI, gives a compound of Formula Ilia.
C
The compound of Formula Ilia can be reduced to give intermediate of Formula IV.
According to yet another embodiment the above process further comprises converting an intermediate of Formula IV to a compound of Formula V (e.g., caspofungm), or pharmaceutically acceptable salts thereof.
According to a preferred embodiment of the present invention Ri is hydrogen and R2 is Ci-C20alkyl group, preferably -(CH2)SCH(CH3)CH2CH(CH3)CH2CH3).
The present invention also provides a process for preparing a compound of Formula V,
and/or pharmaceutically acceptable salts thereof, wherein R2 is Ci C2o alkyl, Ci-C2O alkoxy, C2-C2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, ammo, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl.
The process comprises the steps of: a) reacting a compound of Formula I with cyanuric chloride
to give a compound of Formula II;
b) reducing a compound of Formula II to a compound of Formula III;
•v
RT
Formula VI
to give a compound of Formula IV; and
d) converting a compound of Formula IV to a compound of Formula V, or pharmaceutically acceptable salts thereof.
In the above process, step a) may be carried out in a solvent including a polar aprotic solvent (e.g., dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine or
dimethylacetamide), weakly basic solvent (e.g., pyridine, collidine or the like), or a mixture thereof.
Step b) may be carried out in presence of one or more reducing agents including metal hydrides (e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, aluminum hydride, diborane, diisobutyl aluminum hydride or the like), catalytic reducing agents (e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like), or a mixture thereof.
Step c) may be carried out in the presence of an acid in a polar aprotic solvent. The acid may include organic acids (e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid), or mixtures thereof. The polar aprotic solvent may include dimethylformamide, dimethylsulfoxide, acetate (e.g., ethyl acetate or the like), nitriles (e.g., acetonitrile, propionitrile or the like), ketones (e.g., acetone, diethylketone, methylethylketone or the like), or mixtures thereof.
Step d) involves reacting a compound of Formula IV with ethylene diamine and optionally converting the compound of Formula V (wherein Ri is hydrogen, R2
-(CH2)SCH(CH3)CH2CH(CH3)CH2CH3) to a pharmaceutically acceptable salt such as caspofungin diacetate using acetic acid in ethanol. The present invention further provides a compound having the structure of
Formula IV
and/or pharmaceutically acceptable salts thereof, wherein Ri is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, Ci-C4 alkoxy; R2 is Ci_C2o alkyl, Ci-C2O alkoxy, C2-C2O alkenyl,
aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Ci0 alkoxy, aryl or C5-C6 heteroaryl.
According one embodiment of the present invention Rx is hydrogen and R2 is Ci- C20alkyl group, preferably -(CH2)8CH(CH3)CH2CH(CH3)CH2CH3). Having thus described the invention with the reference to the particular preferred embodiment and illustrative examples, those in art can appreciate the modifications to the invention as described and illustrated that do not depart from the spirit and the scope of the invention as disclosed in the specifications. The examples are set forth to aid the understanding of the invention but are not intended to and should not be construed to limit its scope in any way. Absent statement to the contrary, any combination of the specific embodiment described above are consistent with and are encompassed by the present invention.
Examples
Example 1 : Preparation of a Compound of Formula II (wherein R2 is - (CH2)RCH(CH3)CH2CH(CH3)CH2CH3)
Cyanuric chloride (3.11 g; 16.90 mmole) was added to a solution of Pneumocandin B0 (20 g, 18.78 mmole) in dry dimethylformamide (200 mL; water content below 0.10% (w/w)) at about -30° C for about 20 hours. After the completion of reaction, water (200 mL) was added over 15 minutes and the mixture was warmed to room temperature. The above mixture was slowly poured into vigorously stirred water (2400 mL) at ambient temperature. The suspension was stirred for about 2 hours and filtered. The product was thoroughly washed with water and dried to obtain crude solid (18.4 g), which was further crystallized from solvent mixture of methanol: water: ethyl acetate in the ratio 55: 2.75: 220 mL. Dry Weight = 10 g % Yield = 50%
HPLC purity = 95%
Example 2: Preparation of a Compound of Formula III (wherein R7 is - (CH7)RCH(CHOCH7CH(CHOCH7CHO
To a solution of compound of Formula II (Example 1; 9.95 g, 9.50 mmole) and nickel chloride hexahydrate (NiCl2-OH2O; 9.04 g, 38.03 mmole) in methanol (99.5 rnL) sodium borohydride (7.17 g, 190.18 mmole) was added in lots at a temperature range of about -10° C to about 0° C. The reaction mixture was stirred at 0° C until the starting material was around 2%.
After recovery of methanol at room temperature, reaction mixture was poured into ortho phosphoric acid solution in water (7%; 373 mL) at about 0° C. After the addition of tetrahydrofuran (200 mL), the above suspension was stirred at about 0° C to 5° C for 3 to 4 hours. The above solution was saturated with sodium chloride (55 g). The organic layer was separated and mixed with water (300 mL) at a temperature range of about 5° C to 10° C. The pH of the mixture was adjusted to about 6.5 using sodium bicarbonate solution in water (5%; 140 mL). The above suspension was stirred at a temperature range of about 5° C to 10° C for about 1 hour. The solid was isolated by filtration further washed with acetonitrile (50 mL) and dried at room temperature.
Dry Weight = 9.90 g % Yield = 99
HPLC purity = 88% Example 3: Preparation of a Compound of Formula IV (wherein R7 is - (CH7)sCH(CH0CH7CH(CH0CH7CH0
Commercially available dry 1 -hydroxy benzotriazole (3.21 g, 23.76 mmole; Aldrich sigma) was added to a suspension of a compound of Formula III (Example 2; 5.0 g, 4.76 mmole) in dry acetonitrile (140 mL) at around about -10° C. Trifluoroacetic acid (14.0 ml) was added to the reaction mixture at a temperature below about -5° C and reaction mixture was stirred at a temperature range of about -1° C to 0° C until the content of the compound of the Formula III was below 2% in the reaction mixture (ca. 24 hours). Pre-cooled water (0° C; 280 mL) was added to the reaction mixture maintaining the temperature below 0° C. The pH of the above suspension was adjusted to about 6.5 using saturated dipotassium hydrogen phosphate (K2HPθ4; 100 mL) at 0° C. After decanting the
upper clear solution, sticky solid thus obtained was stirred with water (50 ml) at room temperature for 1 hour and the solid was filtered. The solid was collected and dried at room temperature.
Dry Weight = 4.36 g % Yield = 78.5
Example 4: Preparation of Caspofungin
The compound of Formula IV [Example 3; 5.0 g, 4.28 mmole) was added to ethylene diamine (16 mL) at a temperature range of about 10° C to about 15° C. The resulting solution was stirred for about 1 hour at 10° C to 15° C. The above solution was poured into acetonitrile (160 mL) at room temperature and stirred for 30 minutes at room temperature. After decanting the upper clear solution, fresh acetonitrile (100 mL) was added and stirred for 30 minutes at room temperature. After decanting the upper clear solution, water (100 mL) was added and stirred for about 1 hour at room temperature. The solid was isolated by filtration and washed with water (25 mL). Dry Weight = 3.7 g
The above solid was purified by reverse phase chromatography using the acetonitrile and orthophosphoric acid (0.1% in water) as eluent in the ratio 20:80. The rich cuts were combined and concentrated to provide 0.5 g of compound of Formula V with 97% HPLC purity. Alternatively, the above solid can be purified by reverse phase chromatography using acetonitrile and acetic acid (0.1% in water) as eluent in the ratio 20:80.
Example 5: Preparation of Caspofungin Diacetate
The compound of Formula V (Example 4; 0.20 g) was dissolved in ethanol (2.30 mL) and water (0.20 mL) at room temperature. To this solution was added acetic acid (0.012 mL) at about 10° C followed by slow addition (1 hour) of ethyl acetate (5.0 mL). After stirring at room temperature for 30 minutes, the solid was filtered under inert atmosphere to get caspofungin diacetate.
Dry Weight = 0.12 g % Yield = 60
HPLC purity = 95%
1H NMR (400 MHz, CD3OD): δ 7.12 (d, 2H), 6.75 (d, 2H), 4.98 (bs, IH), 4.91 (d, IH), 4.67 (bs, IH), 4.60-4.43 (m, 4H), 4.31 (bs, 3H), 4.26-4.16 (m, 2H), 4.10-3.95 (m, 3H), 3.85-3.73 (m, 2H), 3.10-2.72 (m, 6H), 2.48-2.36 (dd, IH), 2.30-2.15 (m, 3H), 2.11-1.78 (m, 5H), 1.90 (s, 6H), 1.58 (m, 2H), 1.53-1.19 (m, 15H), 1.16 (d, 3H), 1.13-1.00 (m, 2H), 0.98-0.84 (m, 10H).
13C NMR (100 MHz, CD3OD): 5180.1, 176.4, 174.2, 173.7, 173.5, 172.7, 172.7, 168.9, 158.5, 133.0, 129.6 (2C), 116.2 (2C), 77.3, 75.6, 75.1, 72.1, 71.3, 70.2, 69.3, 68.2, 64.4, 62.7, 58.4, 57.1, 56.2, 56.1, 51.2, 47.1, 45.9, 43.9, 40.3, 39.0, 38.5, 38.1, 36.9, 35.8, 34.6, 32.9, 31.2, 31.1, 30.8, 30.8, 30.6, 30.3, 30.3, 28.0, 27.1, 24.1, 20.7, 20.2, 19.9, 11.5.
IR (KBr, Cm"1): 1631, 1547, 1456, 1411, 1236, 1088. Mass (m/z): 1093.8 (M + H+), 1094.8 (M + 2H+)
Claims
WE CLAIM 1. A process for preparing a novel intermediate of Formula IV,
or pharmaceutically acceptable salts thereof, wherein Ri is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, Ci -C4 alkoxy; R2 is Ci-C2O alkyl, Ci-C2O alkoxy, C2-C2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, aryl or Cs-Coheteroaryl, the process comprising the steps of: a) converting a compound of Formula I
2. The process according to claim 1 , further comprising the step of treating a compound of Formula I with one or more dehydrating agents in a solvent to give a compound of Formula II.
3. The process according to claim 2, wherein the one or more dehydrating agents comprises from cyanuric chloride, oxalyl chloride, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride or chlorosulfonyl isocyanate.
4. The process according to claim 3, wherein the dehydrating agent comprises cyanuric chloride.
5. The process according to 2, wherein the solvent comprises a polar aprotic solvent or a weakly basic solvent.
6. The process according to 5, wherein the polar aprotic solvent comprises dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine or dimethylacetamide.
7. The process according to claim 2, further comprises reducing the compound of Formula II in the presence of one or more reducing agents to give a compound of Formula III.
8: The process according to claim 7, wherein the reducing agent comprises sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, lithium aluminum hydride or diisobutyl aluminum hydride.
9. The process according to claim 8, wherein the reducing agent comprises sodium borohydride with nickel chloride hexahydrate.
10. The process according to claim 1, wherein step b) is carried out in the presence of an acid in a solvent.
11. The process according to claim 10, wherein the acid comprises acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture thereof.
12. The process according to claim 11, wherein the acid comprises trifluoroacetic acid.
13. The process according to claim 10, wherein the solvent comprises dimethylformamide, dimethylsulfoxide, alkyl acetates, nitriles, ketones, or a mixture thereof.
14. The process according to claim 13, wherein the polar aprotic solvent comprises a acetonitrile or propionitrile.
15. The process according to claim 1, further comprising converting a compound of Formula IV to a compound of Formula V, or pharmaceutically acceptable salts thereof.
16. A process for the preparation of a compound of Formula V,
or a pharmaceutically acceptable salt thereof, wherein R2 is Ci-C2O alkyl, Ci-C2O alkoxy, C2-C2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl. The process comprising the steps of: a) reacting a compound of Formula I with cyanuric chloride
Formula VI to give a compound of Formula IV, and
17. The process according to claim 16, wherein step a) is carried out in a solvent comprising a polar aprotic solvent, a weakly basic solvent, or a mixture thereof.
18. The process according to claim 17, wherein the polar aprotic solvent comprises dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine, or dimethylacetamide.
19. The process according to claim 16, wherein step b) is carried out in presence of one or more reducing agents comprising sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, lithium aluminum hydride, or diisobutyl aluminum hydride.
20. The process according to claim 19, wherein the reducing agent comprises sodium borohydride with nickel chloride hexahydrate.
21. The process according to claim 16, wherein step c) is carried out in presence of an acid comprising from acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture thereof.
22. The process according to claim 21, wherein the acid comprises trifluoroacetic acid.
23. The process according to claim 16, wherein step c) is carried out in a polar aprotic solvent comprising dimethylformamide, dimethylsulfoxide, alkyl acetates, nitriles, ketones, or a mixture thereof.
24. The process according to claim 23, wherein the polar aprotic solvent comprises acetonitrile, or propionitrile.
25. The process according to claim 16, wherein step d) comprises reacting a compound of Formula IV with ethylene diamine.
26. The process according to claim 16, wherein the compound of Formula V is caspofungin.
27. A compound having the structure of Formula IV
or pharmaceutically acceptable salts thereof, wherein Ri is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, Ci -C4 alkoxy; R2 is Ci-C2O alkyl, Ci-C2O alkoxy, C2-C2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, C1-C10 alkyl, Ci-Qo alkoxy, aryl, or Cs-Ceheteroaryl.
28. The compound according to claim 27, wherein Rx is hydrogen and R2 is - (CH2)SCH(CH3)CH2CH(CH3)CH2CH3).
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DE112011103711T5 (en) | 2010-11-10 | 2013-08-08 | Shanghai Techwell Biopharmaceutical Co., Ltd. | Caspofungin analogous method of preparation and use thereof |
DE112011103715T5 (en) | 2010-11-10 | 2013-08-29 | Shanghai Techwell Biopharmaceutical Co., Ltd. | Production method for caspofungin |
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KR101596554B1 (en) | 2010-07-20 | 2016-02-22 | 샹하이 테크웰 바이오파마슈티컬 컴퍼니, 리미티드 | Preparation method and use of a crystal of a peptide substance |
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DE112011103711T5 (en) | 2010-11-10 | 2013-08-08 | Shanghai Techwell Biopharmaceutical Co., Ltd. | Caspofungin analogous method of preparation and use thereof |
DE112011103715T5 (en) | 2010-11-10 | 2013-08-29 | Shanghai Techwell Biopharmaceutical Co., Ltd. | Production method for caspofungin |
US9446091B2 (en) | 2011-04-22 | 2016-09-20 | Shanghai Techwell Biopharmaceutical Co., Ltd. | Caspofungin or salts thereof with high purity, as well as preparation method and use thereof |
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