EP2909327A1 - Procédé de préparation de dérivés d'indoline - Google Patents

Procédé de préparation de dérivés d'indoline

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Publication number
EP2909327A1
EP2909327A1 EP13780341.7A EP13780341A EP2909327A1 EP 2909327 A1 EP2909327 A1 EP 2909327A1 EP 13780341 A EP13780341 A EP 13780341A EP 2909327 A1 EP2909327 A1 EP 2909327A1
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EP
European Patent Office
Prior art keywords
transaminase
group
formula
compound
arthrobacter
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP13780341.7A
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German (de)
English (en)
Inventor
Sven NIERDINGER
Ferdinand Zepeck
Wolfgang Kroutil
Robert Simon
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Sandoz AG
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Sandoz AG
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Publication date
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Priority to EP13780341.7A priority Critical patent/EP2909327A1/fr
Publication of EP2909327A1 publication Critical patent/EP2909327A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom

Definitions

  • the present invention relates in general to the field of organic chemistry, and in particular to the preparation of indoline derivatives. These indoline derivatives can be used as
  • silodosin (1 -(3-hydroxypropyl)-5-[(2R)-( ⁇ 2- [2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl ⁇ amino)propyl]indoline-7-carboxamide) is an ch-adrenoceptor antagonist with high uroselectivity, which is particularly suitable for the treatment of benign prostatic hyperplasia.
  • JP2001 -199956 discloses a process for preparation of silodosin, in which process
  • (fi)-5-(2-aminopropyl)-1 -(3-benzoyloxypropyl)-indoline-7-carbonitrile of formula is prepared via a three step reaction.
  • a first step 1 -(3-benzoyloxypropyl)-5-(2-oxo propyl)- indoline-7-carbonitrile and (R)-2-phenyl ethylamine are reacted under acid catalysis in order to obtain the corresponding imine.
  • the imine is reduced under a hydrogen atmosphere in the presence of platinum oxide catalyst, wherein the resulting reaction mixture is hydrogenated in the presence of Pd on charcoal in a third step.
  • the object of the present invention is to provide an improved process for preparing indoline derivatives representing valuable key intermediates for the preparation of pharmaceutically active agents such as silodosin or derivatives thereof.
  • CN is selected from the group consisting of CN, NH 2 , N0 2, halogen and a group convertible to carbamoyl,
  • hydroxy protecting group means any group known in the art which can be used for protecting a hydroxy group, with the proviso that the cleavage conditions for selectively removing said hydroxy protecting group will not adversely affect the structure of compound of formula I I or a derivative thereof.
  • amino protecting group means any group known in the art which can be used for protecting an amino group, with the proviso that the cleavage conditions for selectively removing said amino protecting group will not adversely affect the structure of compound of formula I I or a derivative thereof.
  • alkyl as used herein means straight, branched or cyclic hydrocarbons.
  • aryl as used herein means hydrocarbon aryls, preferably single or condensed six- membered rings, more preferably phenyl or naphthyl, in particular phenyl.
  • alkylaryl as used herein means that the aforementioned aryl moieties are incorporated into the aforementioned straight or branched alkyl moieties either at one of the proximal or distal ends of the alkyl chain or between the aforementioned alkyl chains.
  • proximal end means for e.g. adjacent to the indoline ring moiety of compound of formula I or I I, while distal means the terminal carbon of the alkyl moiety which is furthermost from said indoline ring moiety.
  • substituted as employed herein means that one or more, preferably 1-3 hydrogen atoms of a structural moiety are replaced independently from each other by the
  • substituents include, without being limited thereto, for example halogen, trifluoromethyl, cyano, nitro, -NR', -OR', -N(R')R" and R'", wherein each of R', R" and R'" are selected from the group consisting of linear or branched C1 - C6 alkyl.
  • substituent(s) are at positions where their introduction is/are chemically possible, that is positions being known or evident to the person skilled in the art to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • substituents which may be unstable or may affect reactions disclosed herein may be omitted.
  • R 4 and R 5 are unsubstituted.
  • ⁇ -transaminase as used herein means an enzyme converting a keto compound into an amino compound and vice versa, ⁇ -transaminase belongs to the class of enzymes having the Enzyme Commission (EC) number EC 2.6.1.
  • amine donor means a compound which donates its amino group to a substrate in a transamination reaction, wherein the amino group of the amine donor is converted to a keto group.
  • ⁇ -transaminase is (R)-selective, preferably, the (R)-selective ⁇ -transaminase is derived from an organism selected from the group consisting of (R)-Arthrobacter sp., Hyphomonas neptunium,
  • Aspergillus terreus and Arthrobacter round 1 1 mutant preferably (R)-Arthrobacter sp. and Aspergillus terreus, more preferably (R)- Arthrobacter sp.
  • (R)-selective means ⁇ -transaminase enzymes which selectively or essentially selectively convert the prochiral carbonyl substrate of formula I to the respective amine compound of formula II in form of its (fi)-enantiomer.
  • Arthrobacter round 11 mutant means a mutant which was obtained and identified after the eleventh round of mutation in the process for preparing Arthrobacter mutant disclosed in C. K. Savile et al., Science 2010, 329, p. 305-309.
  • ⁇ -transaminase is derived from an organism selected from Chromobacterium violaceum, Hyphomonas neptunium, Bacillus megaterium, (R)- Arthrobacter sp. , Aspergillus terreus, Pseudomonas putida, Pseudomonas fluorescens, and Arthrobacter citreus, preferably Pseudomonas fluorescens and (R)- Arthrobacter sp.
  • the ⁇ -transaminase enzymes defined in items (2) and (3) above may be derived from the above indicated bacteria and fungi in their original, natural form, or in a modified, so-called mutant form.
  • mutant refers to mutants comprising a deletion(s), substitution(s), addition(s), or insertion(s) of one or more, preferably one or several, amino acids in the amino acid sequences or partial sequences thereof; or mutants showing about 80% or more, about 85% or more, preferably about 90% or more, more preferably about 95% or more, about 97% or more, about 98% or more, or about 99% or more identity with the amino acid sequences or partial sequences thereof.
  • mutants include homologs of bacterial or fungal species differing from natural bacteria or fungi and natural mutants thereof such as mutants based on polymorphic mutation among bacteria or fungi of the same species (e.g., race).
  • mutants refers to an integer of 10, 9, 8, 7, 6, 5, 4, 3, or 2.
  • mutants may be preferably selected from those disclosed in C. K. Savile et al., " Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture", Science 2010, 329, p. 305-309.
  • amine donor is selected from the group consisting of alanine, 1 -ethylamin, 1 -propylamine, 2- propylamine, 1 -indolamine, phenethylamine and others, preferably alanine and 2- propylamine, more preferably 2-propylamine.
  • optically active means enantiopure enantiomer or a mixture of enantiomers of the same compound, in which mixture the quantitative content of one enantiomer predominates.
  • optically active means that compound of formula II has an enantiomeric excess as defined in item (6) below.
  • enantiomeric excess means the difference between the percentage of one enantiomer of an optically active compound and the percentage of the other enantiomer of the same optically active compound. For example, an optically active compound which contains 75% R-enantiomer and 25% S-enantiomer will have an enantiomeric excess of 50% of R-enantiomer.
  • the ⁇ -transaminase is provided in the form of permeabilized E. coli cells overexpressing the ⁇ -transaminase or as a crude enzyme extract or a freeze-dried residue thereof or as a (partially) purified enzyme preparation or a freeze-dried residue thereof or as an immobilized preparation, preferably the ⁇ -transaminase is provided in the form of permeabilized E. coli cells overexpressing the ⁇ -transaminase, more preferably a freeze-dried residue of any enzyme solution.
  • overexpressing the ⁇ -transaminase in any form mentioned in item (10) to the molar amount of compound of formula I is 10 g/1 mol to 2000 g/1 mol.
  • reaction mixture further comprises alanine dehydrogenase (Ala- DH), formate dehydrogenase (FDH), nicotinamide adenine dinucleotide (NAD + ), pyridoxal-5 ' -phophat (PLP) and ammonium formate.
  • Al- DH alanine dehydrogenase
  • FDH formate dehydrogenase
  • NAD + nicotinamide adenine dinucleotide
  • PDP pyridoxal-5 ' -phophat
  • the reaction mixture further comprises alanine dehydrogenase (Ala- DH), glucose dehydrogenase (GDH), nicotinamide adenine dinucleotide (NAD + ), pyridoxal-5 ' -phophat (PLP) and glucose and ammonium salts, or alternatively, the reaction mixture further comprises alanine dehydrogenase (Ala-DH), phosphite dehydrogenase (PTDH), nicotinamide adenine dinucleotide (NAD + ), pyridoxal-5 ' - phophat (PLP) and ammonium phosphite.
  • R 3 is a hydroxy protecting group or H
  • R and R 5 are independently from each other selected from substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C3-C10 aryl or substituted or unsubstituted C3-C10 alkylaryl, which process comprises the steps of:
  • R ⁇ R 2 , R 5 and m are defined as above, and
  • amine acceptor means a keto compound whereon an amino group of the substrate is transferred in transamination reaction, wherein the keto group of the amine acceptor is converted to an amine group.
  • first and second type of enantiomers means that in a mixture of (R)- and (S)- enantiomers of compound of formula II, one enantiomer, e.g. the (fi)-enantiomer represents the first type of enantiomer, while the (S)-enantiomer represents the second type of enantiomer, or vice versa.
  • the first type of enantiomer is the (S)-enantiomer of compound of formula II
  • the second type of enantiomer is the (fi)-enantiomer of compound of formula II.
  • ⁇ -transaminase is (S)-selective, preferably the (S)-selective ⁇ -transaminase is derived from an organism selected from the group consisting of Chromobacterium violaceum, Pseudomonas putida I or II, Bacillus megaterium, preferably Pseudomonas putida I and Bacillus megaterium.
  • (S)-selective means that the ⁇ -transaminase enzyme selectively converts an amine substrate in the form of the (S)-enantiomer into the respective carbonyl compound, while there is no or substantially no conversion of an amine substrate in the form of the (fi)-enantiomer.
  • Pseudomonas putida I means a Pseudomonas putida transaminase having a sequence corresponding to Seq. ID 20 disclosed in WO2010/089171 A2
  • Pseudomonas putida II means a Pseudomonas putida transaminase having a sequence corresponding to Seq. ID 22 disclosed in WO2010/089171 A2.
  • Arthrobacter sp. preferably Pseudomonas putida I or II, Aspergillus terreus, Bacillus megaterium and Arthrobacter sp.
  • ⁇ -transaminase enzymes defined in items (15) and (16) above may be derived from the above indicated bacteria and fungi in their original, natural form, or in a modified, so-called mutant form.
  • step i) is optically active.
  • the optically active mixture provided in step i) is prepared according to a process according to any one of items (1) to (13).
  • step i) is a racemic mixture of compound of formula II.
  • racemic mixture means a mixture wherein R- and S-enantiomers are present in equivalent amounts.
  • the racemic mixture is suitably obtained by achiral chemical synthesis.
  • immobilized preparation means that ⁇ -transaminase enzymes are chemically, physically or by means of genetic engineering methods confined at or localized at/in a chemically organic or inorganic support material, wherein catalytic activity of the enzyme is retained and the preparation can preferably be used repeatedly and continuously.
  • overexpressing the ⁇ -transaminase in any form mentioned in item (22) to molar amount of compound of formula II is 10 g/1 mol to 2000 g/1 mol.
  • reaction mixture further optionally comprises an aqueous buffer system selected from the group consisting of phosphate buffer, TRIS buffer, PIPES buffer and HEPES buffer, preferably the buffer system is a phosphate buffer, more preferably a potassium phosphate buffer; most preferably a buffer can be omitted.
  • an aqueous buffer system selected from the group consisting of phosphate buffer, TRIS buffer, PIPES buffer and HEPES buffer, preferably the buffer system is a phosphate buffer, more preferably a potassium phosphate buffer; most preferably a buffer can be omitted.
  • aqueous buffer system means an admixture of a weak acid and its conjugate base or a weak base and its conjugate acid, which admixture is dissolved in water and is capable to stabilize the pH value of an aqueous solution.
  • a "Tris buffer” as used herein means an admixture of e.g. tris(hydroxymethyl)aminomethane (TRIS) and a strong inorganic acid such as hydrochloric acid
  • phophate buffer as used herein means an admixture of e.g. K 2 HP0 4 and KH 2 P0 4
  • PIPES buffer means an admixture of e.g.
  • piperazine- N,N'-bis(2-ethanesulfonic acid) and an alkali hydroxide such as NaOH or KOH and HEPES buffer means an admixture of e.g. 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid (HEPES) and an alkali hydroxide such as NaOH or KOH.
  • HEPES 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid
  • amine protective group selected from the group consisting of tert-butylcarbonyl (Boc), benzyloxycarbonyl (Z), 9-Fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (alloc).
  • the hydroxy protective group R 3 is selected from the group consisting of benzoyl, tosyl, methoxymethyl, tetrahydropyranyl, t-butyl, allyl, benzyl (Bz), t-butylmethylsilyl, t-butyldiphenylsilyl, acetyl, pivaloyl.
  • R 2 ' is -(CH 2 ) 3 -0-R 3 ' or -(CH 2 ) 3 -0-CO-R 4 ', in which R 3 ' and R' 4 represent substituted or unsubstituted C1 -C10 alkyl or substituted or unsubstituted C3-C10 aryl or substituted or unsubstituted C3-C10 alkylaryl, prepared by a process according to any one of items (1 ) to (27), and b) converting the compound of formula II" of step a) to silodosin.
  • R 3 ' and R' 4 represent substituted or unsubstituted C1 -C10 alkyl or substituted or unsubstituted C3-C10 aryl or substituted or unsubstituted C3-C10 alkylaryl, prepared by a process according to any one of items (1 ) to (27), and b) converting the compound of formula II" of step a) to si
  • chiral indoline derivatives are synthesized by means of chemical synthesis affording the desired indoline derivative in the form of a racemat. Therefore, in order to obtain enantiomerically enriched or pure indoline derivative, in conventional processes, it is necessary to subject racemic indoline derivatives to resolution of racemates. Resolution of racemates is a laborious procedure, since it typically requires multiple subsequent resolution steps in order to obtain a satisfactory high degree of enantioenrichment. These multiple resolution steps in turn result in relatively poor yields of enantiomerically enriched or enantiopure product.
  • EP 0 987 332 A1 describes the use of a ⁇ -transaminase derived from Arthrobacter sp. for transamination of a substrate having the structural formula
  • 807-813 describes a screening of several putative (R)-selective amine transaminases for asymmetric synthesis of 2-aminohexane, 2-amino-4- phenylbutane, 1 -N-Boc-3-aminopyrrolidine and 1 -N-Boc-3-amopiperidine from the corresponding ketones.
  • R 3 is a hydroxy protecting group or H
  • R and R 5 are independently from each other selected from substituted or unsubstituted C1 -C10 alkyl or substituted or unsubstituted C3-C10 aryl or substituted or unsubstituted C3-C10 alkylaryl,
  • indoline compounds of formula I or II represent valuable (intermediate) compounds in the field of pharmacy and have been surprisingly found, albeit their complex structure, to be susceptible substrates of ⁇ -transaminase enzymes, and even further surprisingly with achieving enantiomeric excess combined with beneficial properties, such as purity and/or yield.
  • compound of formula II wherein
  • F is selected from the group consisting of CN, NH 2 , N0 2 and a group convertible to carbamoyl,
  • R 3 is a hydroxy protecting group
  • R and R 5 are independently from each other selected from substituted or unsubstituted C1 -C10 alkyl or substituted or
  • the procedural concept according to this aspect of the invention provides for a compound of formula II representing a highly valuable intermediate for the preparation of pharmaceutically active agents such as silodosin or derivatives thereof. It was surprisingly found by the present inventors that compound of formula I is converted via enzymatically catalysed reductive transamination reaction to compound of formula II, which conversion surprisingly can be effected, depending on further suitable conditions such as enzyme type selection, the procedural concept of reductive amination or kinetic resolution respectively provides for enantiomeric excess with a good combination of high yield and chemical purity.
  • the ⁇ -transaminase is (R)-selective, and preferably, the (R)-selective ⁇ -transaminase is derived from an organism selected from the group consisting of Arthrobacter sp. , Aspergillus terreus, Pseudomonas putida and Arthrobacter round 1 1 mutant, in particular the (R)-selective ⁇ -transaminase is (R)- Arthrobacter sp. and Aspergillus terreus, more preferably (R)-Arthrobacter sp. and Aspergillus terreus, and in particular (R)- Arthrobacter sp.
  • the ⁇ -transaminase is suitably selected in order to obtain the (fi)-enantiomer of compound of formula II.
  • (R)-selective ⁇ -transaminases enantioselectively convert the prochiral substrate compound of formula I into the (fi)-enantiomer of compound of formula II.
  • compound of formula II represents e.g. an intermediate for silodosin
  • the (R)- enantiomer is particularly preferred, since in case of silodosin, this enantiomer is approved e.g. by the Federal Drug Administration (FDA) of the United States as pharmaceutically active agent.
  • FDA Federal Drug Administration
  • the ⁇ -transaminase is derived from an organism selected from Chromobacterium violaceum, Hypophomonas neptunium, Bacillus megaterium, Arthrobacter sp., Aspergillus terreus, Pseudomonas putida, Pseudomonas fluoresceins, Arthrobacter citreus and Arthrobacter round 1 1 mutant, preferably Pseudomonas fluoresceins and (R)-Arthrobacter sp, preferably (R)-Arthrobacter sp.
  • the optically active form has an enantiomeric excess of at least 60-100%, more preferably 75-100%, even more preferably 85-100%, yet even more preferably 90-100%, still yet even more preferably 95-100% and in particular 99-100%.
  • compound of formula II is obtained in advantageous to exceptionally high enantiomeric excess, preferably in high enantiomeric excess.
  • the amine donor is selected from the group consisting of alanine, 1 -ethylamine, 1 -propylamine, 2-propylamine, 1 -indolamine, phenethylamine and others, preferably alanine and 2-propylamine, more preferably 2- propylamine.
  • the aforementioned compounds represent particularly suitable amine donor compounds.
  • compound of formula I is provided in a concentration of 1 to 200 mM in the reaction mixture, preferably 5 to 150 mM, more preferably 10 to 100 mM and in particular 15 to 50 mM. In this way, conversion rate is significantly improved.
  • ⁇ -transaminase is derived from an organism selected from the group consisting of Chromobacterium violaceum, Bacillus megaterium, Arthrobacter sp., Aspergillus terreus, Pseudomonas putida, Pseudomonas fluorescens and Arthrobacter citreus
  • a relatively low reaction temperature for carrying out the process of 16- 40°C, preferably 20-36°C, more preferably 24-34°C, even more preferably 26-32°C is particularly suitable.
  • the process is preferably carried out at a reaction temperature of 35-50°C, preferably 40-45°C whereby particularly advantageous conversion rates are obtained.
  • the reaction mixture further comprises alanine dehydrogenase (Ala-DH), formate dehydrogenase (FDH), nicotinamide adenine dinucleotide (NAD + ), pyridoxal-5 ' -phophat (PLP) and ammonium formate.
  • Al-DH alanine dehydrogenase
  • FDH formate dehydrogenase
  • NAD + nicotinamide adenine dinucleotide
  • PDP pyridoxal-5 ' -phophat
  • the reaction mixture further comprises alanine dehydrogenase (Ala-DH), glucose dehydrogenase (GDH), nicotinamide adenine dinucleotide (NAD + ), pyridoxal-5 ' - phophat (PLP), glucose and ammonium salts, or according to another alternative, the reaction mixture further comprises alanine dehydrogenase (Ala-DH), phosphite dehydrogenase (PTDH), nicotinamide adenine dinucleotide (NAD + ), pyridoxal-5 ' -phophat (PLP) and ammonium phosphite.
  • a particularly suitable alanine-dehydrogenase cofactor recycling system is provided.
  • R 3 is a hydroxy protecting group
  • R and R 5 are independently from each other selected from substituted or unsubstituted C1 -C10 alkyl or substituted or
  • R ⁇ R 2 , R 5 and m are defined as above, and
  • a further, alternative process for preparing a compound of formula II having enantiomeric excess and good chemical purity, preferably high enantiomeric excess is provided.
  • a mixture of enantiomers of compound of formula II e.g. a racemic mixture thereof, serves as a particularly suitable substrate for efficiently enantiomerically enriching compound of formula II by means of kinetic resolution using ⁇ -transaminase enzymes.
  • ⁇ -transaminase enzymes an individual one, e.g.
  • the undesired enantiomer of the compound of formula II is converted to compound of formula I which can be easily separated by physical and/or chemical methods from compound of formula II, while the other individual one, e.g. the desired enantiomer of compound of formula II is converted a lesser extend, preferably not or at least substantially not converted to compound of formula I.
  • the ⁇ -transaminase is derived from an organism selected from the group consisting of Hyphomonas neptunium, Chromobaterium violaceum, Pseudomonas putida I or II, Aspergillus terreus, Bacillus megaterium and Arthrobacter sp., preferably Pseudomonas putida, Aspergillus terreus, Bacillus megaterium and Arthrobacter sp.
  • the ⁇ -transaminase is (S)-selective, more preferably the (S)-selective ⁇ -transaminase is derived from an organism selected from the group consisting of Chromobacterium violaceum, Pseudomonas putida I or II, Bacillus megaterium, even more preferably Pseudomonas putida I and Bacillus megaterium.
  • the optically active chiral amine of compound of formula II obtained in step ii) has an enantiomeric excess of 70-100%, preferably 80- 100%, more preferably 90-100%, even more preferably 95-100%, yet even more preferably 99-100%.
  • compound of formula II is obtained in advantageous to exceptionally high enantiomeric excess, preferably in high enantiomeric excess.
  • the kinetic resolution process is carried out at a reaction temperature of 16-40°C, preferably 20-36°C, more preferably 24-34°C, even more preferably 26-32°C.
  • a molar ratio of compound of formula II to amine acceptor is 1 : 1 to 1 : 10, preferably 1 : 1.2 to 1 :8, more preferably 1 : 1.2 to 1 :4, most preferably 1 : 1.5 to 1 :2.5;
  • the ⁇ -transaminase overexpressing the ⁇ -transaminase or as a crude enzyme extract or a freeze-dried residue thereof or as a (partially) purified enzyme preparation or a freeze-dried residue thereof or as an immobilized preparation, preferably the ⁇ -transaminase is provided in the form of permeabilized E. coli cells overexpressing the ⁇ - transaminase, more preferably a freeze-dried residue of any enzyme solution;
  • the process is carried out in the presence of an organic solvent selected from the group consisting of DMF, DMSO, THF, MeCN, 1 ,2-dimethoxy ethane (DME), and C1 - C6-alcohols, preferably DMF, DMSO, THF, MeCN, DME and C1 -C3-alcohols, more preferably DMF, DMSO, TH F, MeCN, DME, in particular DMF and DMSO;
  • an organic solvent selected from the group consisting of DMF, DMSO, THF, MeCN, 1 ,2-dimethoxy ethane (DME), and C1 - C6-alcohols, preferably DMF, DMSO, THF, MeCN, DME and C1 -C3-alcohols, more preferably DMF, DMSO, TH F, MeCN, DME, in particular DMF and DMSO;
  • the reaction mixture further optionally comprises an aqueous buffer system selected from the group consisting of phosphate buffer, TRIS buffer, PI PES buffer and HEPES buffer, preferably the buffer system is a phosphate buffer, more preferably a potassium phosphate buffer; most preferably a buffer can be omitted;
  • an aqueous buffer system selected from the group consisting of phosphate buffer, TRIS buffer, PI PES buffer and HEPES buffer, preferably the buffer system is a phosphate buffer, more preferably a potassium phosphate buffer; most preferably a buffer can be omitted;
  • R 2 represents an amine protective group selected from the group consisting of tert- butylcarbonyl (Boc), benzyloxycarbonyl (Z), 9-Fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (alloc);
  • the hydroxy protective group R 3 is selected from the group consisting of benzoyl, tosyl, methoxymethyl, tetrahydropyranyl, t-butyl, allyl, benzyl (Bz), t-butylmethylsilyl, t- butyldiphenylsilyl, acetyl, pivaloyl; and
  • any one of features (i) to (viii) represents particularly advantageous process conditions.
  • feature (iv) it was surprisingly found that the appropriate choice of solvent significantly improves conversion rate.
  • silodosin having the formula HO
  • R 2 ' is -(CH 2 ) 3 -0-R 3 ' or -(CH 2 ) 3 -0-CO-R 4 ', in which R 3 ' and R 4 ' represent substituted or unsubstituted C1 -C10 alkyl or substituted or unsubstituted C3-C10 aryl or substituted or unsubstituted C3-C10 alkylaryl, prepared by a process according to any one of items (1) to (27) indicated above, and
  • step b) converting the compound of formula II" of step a) to silodosin.
  • the above mentioned aspect provides a particularly advantageous process for preparing silodosin owing to the application of the present procedural aspects of reductive amination and/or kinetic resolution and the beneficial effects involved therewith.
  • a pharmaceutical formulation which comprises silodosin of formula
  • silodosin is entirely free of metal impurities.
  • metal impurities as used herein means impurities deriving from a catalyst in the form of elemental metal, covalent metal compounds or metal compounds in the form of a salt used in conventional chemical syntheses for preparing silodosin. More specifically, “metal impurities” are meant to be derived from metal catalysis conventionally applied in the chemical preparation of silodosin, in which typically e.g. Pd on charcoal and/or Pt0 2 on BaS0 4 is/are applied.
  • pharmaceutically acceptable excipient means any physiologically inert, pharmacologically inactive material known in the art being compatible with the physical and chemical characteristics of the active agent.
  • amino acid sequence of the below listed ⁇ -transaminases originates from the indicated literature, however, the present inventors employed codon optimized genes for improved expression of ⁇ -transaminase in E. coli.
  • Pseudomonas putida I corresponds to Seq. ID 20
  • P seudomonas putida II to Seq. ID 22.
  • ⁇ -transaminase derived from Arthrobacter citreus was taken from WO 2006 / 063336 (or we us US 7247460 B2).
  • Arthrobacter citreus corresponds to Sep. ID:02 in this patent.
  • All ⁇ -transaminases were expressed in Escherichia coli.
  • the ⁇ -transaminases are applied in form of lyophilized E. coli cell preparations.
  • n.d. means "not determined", and in this single case, deviation between the two determinations was > 10%; Pseudomonas putida listed under
  • the reductive amination process according to the present invention is particularly suitable to obtain the desired product in enantioenriched form.
  • the ⁇ -transaminases is derived from Pseudomonas fluorescens and (R)- Arthrobacter sp. providing both high enantiomeric excess and a high conversion rate. More beneficially, the ⁇ -transaminases is derived from (R)- Arthrobacter sp. providing the (fi)-enantiomer of compound of formula II' representing a highly desirably intermediate product for the preparation of silodosin in both high
  • Lyophilized cells of E. coli containing overexpressed ⁇ - ⁇ derived from Arthrobacter round 1 1 mutant (20 mg and 40 mg respectively) were rehydrated in a potassium phosphate buffer (pH 7.0, 100 mM) containing PLP (1 mM) at room temperature for 30 minutes.
  • the substrate was added afterwards (10 and 25 mM resectively) together with 10 vol% DMSO, and 2- propylamine (250 mM) as N-donor in amount determined by the ratio n(substrate)/n(donor), and the reaction was carried out at 45°C in an Eppendorf orbital shaker (700 rpm) for 24 h.
  • Arthrobacter round 11 mutant are obtained with the conditions according to entry 4 in terms of enantiomeric excess, and the conditions according to entry 1 in terms of conversion. At the conditions according to entry 2, preferably both enantiomeric excess and conversion are well balanced.
  • Exemplary preparative procedure for preparative scale batch Lyophilized cells of E. coli containing overexpressed ⁇ - ⁇ from (R)- Arthrobacter sp. (225 mg) were rehydrated in a KPi buffer (9 mL, pH 7.0, 100 mM) containing PLP (1.00 mM), NAD + (1.00 mM), ammonium formate (150 mM), FDH (1 1 U), Ala-DH (12 U) and D-alanine (500 mM) at 22°C for 30 minutes.
  • Pseudomonas putida I which provides the (fi)-enantiomer of compound of formula II' representing a highly desirably intermediate product for the preparation of silodosin in both relative high enantiomeric excess and relative high yield.

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  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

La présente invention concerne en général le domaine de la chimie organique, et en particulier la préparation de dérivés d'indoline. Ces dérivés d'indoline peuvent être utilisés en tant qu'intermédiaires dans la synthèse d'agents pharmaceutiquement actifs, tels que la silodosine ou des dérivés de celle-ci.
EP13780341.7A 2012-10-18 2013-10-18 Procédé de préparation de dérivés d'indoline Withdrawn EP2909327A1 (fr)

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EP13780341.7A EP2909327A1 (fr) 2012-10-18 2013-10-18 Procédé de préparation de dérivés d'indoline

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EP12189100 2012-10-18
PCT/EP2013/071820 WO2014060571A1 (fr) 2012-10-18 2013-10-18 Procédé de préparation de dérivés d'indoline
EP13780341.7A EP2909327A1 (fr) 2012-10-18 2013-10-18 Procédé de préparation de dérivés d'indoline

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ES2607639B1 (es) 2015-09-30 2018-02-28 Urquima, S.A Sal de ácido maleico de un intermedio de silodosina
CN106754806B (zh) * 2016-12-20 2020-04-14 尚科生物医药（上海）有限公司 一种改进的转氨酶及其在(r)-3-氨基丁醇制备上的应用
CN112094830B (zh) * 2017-11-15 2022-06-24 凯莱英生命科学技术(天津)有限公司 转氨酶突变体及其应用
CN109486785B (zh) * 2018-11-30 2020-06-09 江南大学 一种催化效率提高的ω-转氨酶突变体及其应用
CN109486783B (zh) * 2018-11-30 2020-06-09 江南大学 一种可催化西他沙星五元环中间体的ω-转氨酶突变体
CN115838349B (zh) * 2023-02-20 2023-07-14 南京桦冠生物技术有限公司 一种3-(7-氰基-5-(2-氧代丙基)吲哚啉-1-基)苯甲酸丙酯的制备方法

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