Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a process for preparing silodosin with high optical purity.
• Silodosin is commercially available under the tradenames RAPAFLO® or UROREC® as a capsule formulation for oral use containing 4 mg or 8 mg of the drug. The capsules are to be taken orally once daily for the treatment of the signs and symptoms of benign prostatic hyperplasia.
• U.S. Pat. No. 5,387,603 and EP 0 600 675 disclose silodosin as a therapeutic agent for the treatment for dysurea associated with benign prostatic hyperplasia. The molecular structure of silodosin (XXV) is shown below.
• silodosin The synthesis of silodosin is relatively complex and requires a sequence of multiple steps.
• a key intermediate compound in the synthesis of silodosin is the optically active amine compound represented by the general formula R-V:
• R 1 represents a protecting group and R 2 represents a cyano (CN) or carbamoyl (CONH 2 ) group.
• the intermediate compound R-V bears the asymmetric carbon atom that imparts the optical activity to silodosin. Therefore, it is important to obtain the compound R-V with high optical purity, because according to the methods reported in the state of the art the optical purity of the compound R-V determines the optical purity of the final product silodosin.
• JP 2001-199956 discloses a process for the preparation of a compound of formula R-V, wherein 1-(3-benzoyloxypropyl)-7-cyano-5-(2-oxopropyl)-2,3-dihydroindole or the corresponding 7-carbamoyl derivative is reacted with an optically active amine, namely L-2-phenylglycinol or L-1-phenylethanamine, to afford an imine compound of formula III as depicted in the below scheme 1.
• an optically active amine namely L-2-phenylglycinol or L-1-phenylethanamine
• the optically active imine III is subjected to catalytic hydrogenation using platinum(IV) oxide as a catalyst affording the diastereomers IV in a ratio of 3.8:1.
• the chiral auxiliary II is subsequently removed by catalytic hydrogenation using 10% palladium on carbon, i.e. under the typical conditions which lead to the cleavage and removal of benzylic protecting groups from nitrogen or oxygen atoms.
• the catalytic deprotection reaction affords the desired intermediate compound R-V with an optical purity corresponding to the ratio of the diasteromers obtained in the previous step, i.e. the ratio of compound R-V to S-V is approximately 3.8:1, which corresponds to an optical purity of approximately 58.3% enantiomeric excess (e.e.).
• the process involves the reaction of an enantiomeric mixture of the compound of formula VI with (1S,2R)-2-benzylaminocyclohexane methanol (VII) to obtain a diastereomeric mixture containing the salt VIII. After a series of crystallizations the diastereomer VIII was obtained with an optical purity of 92.8% diastereomeric excess (d.e.). Subsequently, the salt VIII was treated with an acidic aqueous solution to release the acid R-VI from the salt. After extraction from the aqueous solution with ethyl acetate the acid R-VI is converted into its amide IX. The compound IX is finally subjected to a Hofmann type rearrangement reaction to obtain the desired intermediate compound R-V.
• WO 2011/030356 discloses a process for the preparation of the intermediate compound R-V, which avoids the resolution of the enantiomers of specific intermediate compounds using chiral auxiliaries or optically active bases.
• the route of synthesis described in WO 2011/030356 starts from L-alanine (X), which is a naturally occurring optically active amino acid.
• the process described in WO 2011/030356 is depicted in the below scheme 3.
• the amino acid is protected by the addition of ethyl chloroformate and subsequently activated by the addition of oxalyl chloride to afford R—(N-ethoxycarbonyl)alanine as an acyl chloride (XI).
• Said acyl chloride is reacted with hydroxy protected 1-(3-hydroxypropyl)-7-cyano-2,3-dihydroindole of formula XII in a Friedel-Crafts acylation reaction, which gives a compound of formula XIII.
• the oxo group in compound XIII is reduced to afford a compound of formula XIV that is subsequently subjected to a hydrolysis reaction to yield the key intermediate compound R-V.
• silodosin with sufficiently high optical purity i.e. a silodosin or a pharmaceutically acceptable salt thereof with an optical purity of at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., and most preferred at least 99.9% e.e.
• the key intermediate compound R-V is provided with an optical purity of at least 85% e.e., which affords a crude silodosin with the same optical purity of at least 85% e.e., the crude silodosin can be easily purified by crystallization to obtain the drug with high optical purity. Accordingly, it is not necessary to obtain compound R-V with high optical purity in order to induce a high optical purity in the final product silodosin. It was further found that compound R-V can be obtained with sufficiently high optical purity, i.e. at least 85% e.e., by resolving the enantiomers contained in a racemic mixture of a compound represented by the general formula V:
• R 1 is the protecting group
• R 2 is cyano or carbamoyl
• Suitable hydroxy protecting groups are those well known in the art and which may be removed under conventional conditions without disrupting the remainder of the molecule.
• Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups, such as triC 1-6 -alkylsilyl, e.g. trimethylsilyl (TMS) and tert-butyl dimethylsilyl (TBDMS), organocarbonyl and organooxycarbonyl groups, such as acetyl, benzoyl (COPh), C 1-6 -alkoxycarbonyl and 4-methoxybenzoyl-oxycarbonyl, unsaturated C 2-6 -alkyl groups, such as allyl and propargyl, and the benzyl group (Bn).
• triorganosilyl groups such as triC 1-6 -alkylsilyl, e.g. trimethylsilyl (TMS) and tert-butyl dimethylsilyl (TBDMS)
• the present invention thus relates to a process for preparing silodosin of formula XXV:
• step (a) If in step (a) above the mixture of the compound of formula V is only partially resolved, so that the silodosin or pharmaceutically acceptable salt thereof obtained in method step (c) has an optical purity of between 85% and 95% e.e., preferably between 85% and 98% e.e., the purification of the silodosin obtained in step (c) by crystallization from a solvent is required in order to improve the optical purity up to at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., and most preferred at least 99.9% e.e.
• the solvent used in method step (d) should contain a carboxylic acid ester, preferably is a carboxylic acid ester.
• the carboxylic acid ester is a C1-6-alkyl acetate, e.g. ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or a mixture thereof.
• step (a) The separation of the compound of formula R-V in step (a) may be conducted by
• the optically active acid is L-tartaric acid.
• the water-immiscible solvent used in the extraction step (iv) preferably contains or is a carboxylic acid ester.
• the carboxylic acid ester may be a C 1-6 -alkyl acetate, preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or a mixture thereof.
• the compound V used in the process of the present invention is obtainable by reducing a compound represented by the general formula XX:
• R 1 has the same meaning as defined above.
• the reduction of the compound XX is usually a catalytic hydrogenation using, e.g. platinum on charcoal (e.g. 5% Pt/C) or platinum (IV) oxide as a catalyst.
• the hydroxy protected compound XV i.e. hydroxy protected 1-(3-hydroxypropyl)-2,3-dihydroindole
• DMF dimethylformamide
• POCl 3 phosphoryl chloride
• the aldol condensation with nitroethane gives compound XVII that is subsequently reduced, e.g. with sodium boranate, to afford the nitro compound XVIII.
• An additional formyl group is introduced at position 7 of the indoline moiety in a second Vilsmeier reaction to obtain the compound XIX.
• the intermediate compound XXIV may contain an impurity derived from the reaction of compound R-V with two molecules of compounds XXII or XXIII, i.e. the corresponding tertiary amine.
• the intermediate compound XXIV may be crystallized in form of its oxalic acid addition salt as described in EP 1 806 340 prior to the following deprotection reaction.
• the present invention relates to the use of a racemic mixture of a compound of formula V,
• R 1 is a protecting group
• R 2 is cyano or carbamoyl, for the preparation of silodosin or a pharmaceutically acceptable salt thereof.
• the racemic mixture of the compound of formula V may be subjected to an enantiomeric resolution procedure to obtain a0 compound of formula R-V:
• the silodosin or a pharmaceutically acceptable salt thereof having an optical purity of at least 85% e.e., corresponding to the optical purity obtained in the aforementioned resolution procedure can then be purified by crystallization from a solvent to obtain a silodosin or a pharmaceutically acceptable salt thereof with an optical purity of at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., most preferred at least 99.9% e.e.
• the solvent used for crystallizing silodosin or a pharmaceutically acceptable salt thereof contains a carboxylic acid ester, more preferred is a carboxylic acid ester.
• the carboxylic acid ester include C 1-6 -alkyl acetates as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixtures thereof, most preferred is ethyl acetate, isopropyl acetate or a mixture thereof.
• the compound XXI-tartrate (10.0 g) was neutralized using an aqueous sodium hydroxide solution.
• the compound R-V was extracted with ethyl acetate.
• the ethyl acetate solution containing compound R-V was directly used in the following example 10.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Indole Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 2012
  • 2012-10-19 CN CN201280052935.3A patent/CN104302621A/zh active Pending
  • 2012-10-19 WO PCT/EP2012/004378 patent/WO2013056842A1/en not_active Ceased
  • 2012-10-19 US US14/352,557 patent/US20150038727A1/en not_active Abandoned
  • 2012-10-19 ES ES12783113.9T patent/ES2639196T3/es active Active
  • 2012-10-19 IN IN1030KON2014 patent/IN2014KN01030A/en unknown
  • 2012-10-19 EP EP12783113.9A patent/EP2768806B1/en active Active
• 2015
  • 2015-12-21 US US14/976,140 patent/US9938239B2/en active Active

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