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WO2014128523A1 - Procédé de préparation d'un intermédiaire de flavones substituées par une pyrrolidine - Google Patents

Procédé de préparation d'un intermédiaire de flavones substituées par une pyrrolidine Download PDF

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Publication number
WO2014128523A1
WO2014128523A1 PCT/IB2013/051331 IB2013051331W WO2014128523A1 WO 2014128523 A1 WO2014128523 A1 WO 2014128523A1 IB 2013051331 W IB2013051331 W IB 2013051331W WO 2014128523 A1 WO2014128523 A1 WO 2014128523A1
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formula
compound
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mixture
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Suneelmanoharbabu CHENNAMSETTY
Ravishankar BOKKA
Rathinasami VEERAPPAN
Meenakshi Sivakumar
Sivaramakrishnan Hariharan
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Piramal Enterprises Ltd
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Piramal Enterprises Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a process for the preparation of a key intermediate (as described herein) used in the synthesis of ⁇ +)-trans enantiomer of pyrrolidine substituted flavones, represented by the compounds of formula (1 ) or pharmaceutically acceptable salts thereof; which are inhibitors of cyclin dependant kinases (CDKs) and can be used in the treatment of proliferative disorders such as cancer.
  • a key intermediate as described herein
  • CDKs cyclin dependant kinases
  • the cell-division cycle is a process that is regulated by the cyclin dependent kinases (CDKs). Stringent control of this process is essential to ensure that DNA synthesis and subsequent mitotic division are accurately and coordinately executed (Current Opinion in Genetics & Development, 1999, 9, 104-1 1 1 ).
  • CDKs cyclin dependent kinases
  • Stringent control of this process is essential to ensure that DNA synthesis and subsequent mitotic division are accurately and coordinately executed (Current Opinion in Genetics & Development, 1999, 9, 104-1 1 1 ).
  • CDKs cyclin dependent kinases
  • the overexpression of cyclin D1 leads to the deregulation of CDK4-D1 kinase activity and thereby contributes to uncontrolled cell proliferation.
  • the CDKs, their regulators, and substrates are the targets of genetic alteration in many human cancers. As a result of this, the CDKs have been targeted for drug discovery and a number of small molecule inhibitors of CDKs have been
  • CDK inhibitors namely (+)-trans enantiomer of pyrrolidine substituted flavones have been disclosed in US Patent 7,271 ,193. These compounds have been reported to exhibit good selectivity for inhibition of CDK4-D1 , CDK1 -B and CDK9-T1 and potent antiproliferative effects against various human cancer cell lines (Molecular cancer therapeutics, 2007, 6, 3, 918-925).
  • the compounds disclosed in the aforesaid patent have two chiral centers and hence, can exist as four enantiomers i.e. ⁇ +)-trans, (-)- trans, (+)-c/ ' s and (-)-c/ ' s.
  • the inactive enantiomer shows unwanted side effects or even toxic effects.
  • the chiral switch process (racemate to single enantiomer) has resulted in a number of agents being re-marketed as single enantiomer products.
  • Analytical methods which have been used for enantioseparation include diastereomeric crystallization, biocatalysis, chromatographic techniques (thin layer chromatography, gas chromatography, supercritical and sub-critical fluid chromatography, high-performance liquid chromatography), affinity electrokinetic chromatography and electromigration techniques (capillary electrophoresis and capillary electrochromatography) (International Journal of Pharm. Tech. Research, 2010, 2, 2, 1584-1594).
  • (+)- irans-2-(2-chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)- chromen-4-one was prepared by resolution of an intermediate, namely ( ⁇ )-frans-[1 - methyl-3-(2,4,6-trimethoxy-phenyl)-pyrrolidin-2-yl]-methanol, and subsequent conversion of the ⁇ -)-trans isomer of the intermediate to (+)-frans-2-(2-chlorophenyl)- 5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one.
  • the preparation of the (-)-frans-isomer of the intermediate involves the steps of treating its racemate with a chiral auxiliary to obtain the corresponding (+)- and (-)-trans diastereomeric salts followed by separating the desired diastereomeric salt by crystallization and treating it with a base to yield the desired ⁇ -)-trans enantiomer.
  • This resolution method involves significant processing and also the use of resolving agent renders the process costly. Partial recycling of the resolving agent is feasible but such recycling is costly as it requires additional processing and is also associated with waste generation. The undesired enantiomer cannot be recycled and is therefore discarded.
  • the maximum theoretical yield of the key intermediate obtained is just 50 % on a laboratory scale synthesis due to loss of half of the racemate. This yield may be further reduced due to the need for high chiral purity (> 97 % enantiomeric excess).
  • the present invention provides a process for the preparation of the compound of formula A which is a key intermediate used in the synthesis of the (+)- trans enantiomer of the compounds of formula (1 ).
  • the present invention also involves synthesis of the compounds of formula (1 ) from the compound of formula (A) in an efficient and cost-effective manner.
  • the present invention relates to a process for the preparation of an enantiomerically pure ⁇ -)-trans enantiomer of a compound, represented by formula A (as presented herein); which is a key intermediate (the chiral precursor) of the compound of formula (1 ) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for the preparation of an enantiomerically pure ⁇ +)-trans enantiomer of a compound, represented by formula (1 ) (as presented herein) or a pharmaceutically acceptable salt thereof; from the compound of formula A.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, as well as represents a stable compound, which does not readily undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • racemic or “racemate” refer to generally equimolar proportions of a (+)-enantiomer and a (-)-enantiomer of a compound in a composition.
  • enantiomeric excess refers to a difference between the amount of one enantiomer and the amount of the other enantiomer that is present in the product mixture (racemate).
  • enantiomeric excess of 96 % refers to a product mixture having 98 % of one enantiomer and 2 % of the other enantiomer.
  • enantiomerically pure refers to a compound or compounds that is or are present in enantiomeric excess of greater than 95 %. Preferably, the enantiomeric excess is greater than 97 %. More preferably, the enantiomeric excess is greater than 99 %.
  • substantially free means that the amount of the desired enantiomer predominates in composition relative to the undesired enantiomer.
  • the term “substantially free” means that the amount of the ⁇ +)-trans enantiomer predominates the composition relative to the ⁇ -)-trans enantiomer of the compound of formula (1 ). More specifically, this means that the amount of the ⁇ +)-trans enantiomer relative to the ⁇ -)-trans enantiomer by weight is at least about 95 %, more preferably greater than 97 %.
  • salts of basic or acidic groups of the compound of the invention which groups are capable of forming salts.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts.
  • suitable inorganic acids include: boric acid, perchloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and other inorganic acids known to the person skilled in the art.
  • Suitable organic acids include: acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, ketoglutaric acid, benzenesulfonic acid, glycerophosphoric acid and other organic acids known to the person skilled in the art.
  • the compounds of formula (1 ) which contain acidic groups can be used according to the invention, for example, as alkali metal salts like lithium (Li), sodium (Na), and potassium (K) salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the subject compound which contains a basic or acidic moiety by conventional chemical methods. Generally the salts are prepared by contacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or dispersant or by anion exchange or cation exchange with other salts. Suitable solvents are, for example, esters, ethers, alcohols, ketonic solvents, or mixtures of these solvents.
  • the present invention is specifically directed to a process for the preparation of a compound of formula A, which is a key intermediate used in the synthesis of an enantiomerically pure compound of formula (1 ).
  • the compounds disclosed in the applicant's US Patent 7,271 ,193 have two chiral centers and hence, can exist as four enantiomers namely ⁇ +)-trans, ⁇ -)-trans, (+)-c/ ' s and (-)-c/ ' s.
  • the efficacy of the racemic compound disclosed in the US Patent 7,271 ,193 and its separate enantiomers have been extensively studied. It has been observed that only the ⁇ +)-trans enantiomer is active as a CDK inhibitor.
  • the present invention relates to a process for the preparation of an enantiomerically pure (+)-trans enantiomer pyrrolidines substituted with flavones represented herein by formula (1 );
  • R- ⁇ is a phenyl group, which is unsubstituted or substituted by one or two identical or different substituents selected from: chloro, nitro and trifluoromethyl; or a pharmaceutically acceptable salt thereof; from the compound of formula A.
  • the compounds of formula (1 ) are useful in inhibiting CDKs, particularly CDK4/cyclinD1 complexes and find use as anti-proliferative agent in the treatment of diseases characterized by excessive cell growth such as cancers, immunological disorders involving unwanted proliferation of leukocytes and other proliferative smooth muscle disorders.
  • the process of the present invention primarily involves an improved process for the preparation of a chiral intermediate represented by formula A, which is economical and efficient.
  • the improved process has advantages such as lower reaction temperature and is simple, consistent, cost-effective and avoids use of toxic solvents such as chloroform or carbon tetrachloride.
  • the process of the present invention provides the desired (+)-trans enantiomer represented herein by formula (1 ) in higher yield and better purity.
  • the process of the present invention primarily involves the resolution of a mixture of enantiomers (racemate) to yield a key intermediate represented by formula A using a relatively low amount of a resolving agent.
  • the process of the present invention involves separation of the mixture of enantiomers by coupling of the mixture of enantiomers with a relatively low amount of auxiliary chiral reagent to obtain the corresponding mixture of diastereomeric salts of the (+)- and (-)-enantiomers of formula A, separating the respective diastereomeric salts and converting the diastereomeric salt of the (-)- enantiomer with a base to obtain the free base of the desired (-)-enantiomer of the compound of formula A.
  • the chiral purity of the compound obtained according to the present invention is 97 % ee.
  • step (e) reacting the mixture of compounds as obtained in step (d) with 0.5 to 0.7 eq. of (-)- DBTA ((-)-dibenzoyl tartaric acid monohydrate) as a chiral auxiliary in the presence of 0.3-0.5 equivalent of concentrated HCI in a solvent to yield the crystallized dibenzoyl tartarate salts of (+)- and (-)-frans-[1 -methyl-3-(2,4,6-trimethoxy-phenyl)- pyrrolidin-2-yl]-methanol;
  • step (f) separating the crystallized dibenzoyl tartarate salts of (+)- and (-)- [1 -methyl-3- (2,4,6-trimethoxy-phenyl)-pyrrolidin-2-yl]- methanol obtained in step (e) above and converting the desired (-)-dibenzoyl tartarate salt of compound of formula A to its free base by treatment of the diastereomeric salt with a base in a solvent to obtain the enantiomerically pure ⁇ -)-trans enantiomer of compound of formula A.
  • reaction in step (a) of Scheme 1 A is carried out at a temperature ranging from 25 - 30 °C (room temperature).
  • step (b) of Scheme 1 A is carried out with powdered sodium borohydride, improving the diborane generation and increasing purity of the product, compound of formula V from 70 % to 85 %.
  • the solvent used in step (b) of Scheme 1 A is selected from tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, diethylether or diisopropylether. In one embodiment, the solvent used in step (b) of Scheme 1 A is tetrahydrofuran.
  • step (c) of Scheme 1 A the compound of formula V is subjected to methylsulfonation followed by ring-contraction reaction with a base selected from sodium acetate or potassium acetate in the presence of an alcoholic solvent selected from methanol, ethanol, 1 -propanol, isopropyl alcohol, n-butanol t-butanol, isobutanol or 2-butanol to obtain the compound of formula VII.
  • a base selected from sodium acetate or potassium acetate
  • an alcoholic solvent selected from methanol, ethanol, 1 -propanol, isopropyl alcohol, n-butanol t-butanol, isobutanol or 2-butanol
  • the alcoholic solvent used in the ring-contraction reaction is isopropyl alcohol while the base used is sodium acetate.
  • the compound of formula IX obtained in step (d) of Scheme 1 A by hydrolysis of the compound of formula VII is extracted with an ether selected from diethyl ether, diisopropyl ether or diisobutyl ether to obtain compound of formula IX having an HPLC purity of 95 % a/a.
  • the solvent used for extraction of compound of formula IX is diisopropyl ether.
  • the chiral auxiliary used in the resolution step is (-)-dibenzoyl tartaric acid ((-)- DBTA).
  • (-)-DBTA monohydrate is used.
  • the base used in the resolution step may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate or potassium carbonate.
  • the base used in the resolution step is sodium carbonate or sodium hydroxide.
  • the solvent used in step (e) of Scheme 1 A may be selected from methanol, ethanol, n-propanol, 1 -butanol, 2-butanol, amyl alcohol, isopropanol, acetone or acetonitrile, or a mixture of any one or more of the solvents with water.
  • the process involving resolution of the intermediate compound of Formula A comprises reacting the racemate of the compound of formula A with 0.5 to 0.7 equivalent of (-)-DBTA ((-)-dibenzoyl tartaric acid) as a chiral auxiliary in the presence of 0.3 to 0.5 equivalent of concentrated HCI and alcohol as a solvent.
  • the process involving resolution of the intermediate compound of Formula A comprises reacting the racemate of the compound of formula A with 0.6 equivalent of (-)-DBTA ((-)-dibenzoyl tartaric acid) as a chiral auxiliary in the presence of 0.4 equivalent of concentrated HCI and methanol as the solvent.
  • the solvent used in step (f) of Scheme 1 A is selected from ethyl acetate, isopropyl acetate or methylene dichloride.
  • the solvent used in step (f) of Scheme 1 A is isopropyl acetate. In another embodiment, the solvent used in step (f) of Scheme 1 A is ethyl acetate.
  • the process according to the present invention is simpler and more cost effective than the known process as it involves a single step reaction to obtain the diastereomeric salt, namely the dibenzoyi tartrate salt.
  • the present process involves a single crystallization.
  • use of the chiral auxiliary (-)-DBTA has the advantage in that it is comparatively cheaper than (+)-DBTA, which is used in the process reported in the published US Patent 7,271 ,193.
  • PCT Publication WO2007148158 describes a synthesis of the (+)-trans enantiomer of pyrrolidine substituted flavones with improved yield and purity by using (-)-dibenzoyl tartaric acid ((-)-DBTA) as an auxiliary chiral reagent.
  • the present invention provides the additional advantage that the resolution step was carried out with about 0.6 eq. of (-)-DBTA. Therefore, usage of about 0.4 eq. of the resolving agent (-)-DBTA was avoided, which is desirable as it renders the entire process cost-effective.
  • the present invention relates to a process for the preparation of the compound of formula (1 ) from the key intermediate i.e. (-)-trans enantiomer of the compound of formula A as outlined in the following Scheme 1 B.
  • the Lewis acid catalyst in step (i) of Scheme 1 B is selected from BF 3 . Et 2 0 (boron trifluoride etherate), BF 3 .CH 3 COOH (boron trifluoride-acetic acid), BF 3 .THF (boron trifluoride-tetrahydrofuran), zinc chloride, aluminium chloride or titanium chloride.
  • the preferred Lewis acid catalyst is BF 3 . Et 2 0.
  • the solvent used for extraction in step (i) is selected from dichloromethane or ethyl acetate.
  • the preferred solvent is dichloromethane.
  • the base used in the process of step (ii) of Scheme 1 B is selected from triethylamine, pyridine, N-methyl morpholine or a combination of DCC ( ⁇ , ⁇ '- dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine).
  • the preferred base is triethylamine.
  • the solvent used in step (ii) is selected from dichloromethane, DMF (N,N- dimethylformamide) or THF (tetrahydrofuran).
  • the preferred solvent is dichloromethane.
  • the base used in step (iii) is selected from lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, sodium amide or potassium hydride.
  • the preferred base is sodium hydride.
  • the solvent of step (iii) of Scheme 1 B is selected from DMF, dioxane, NMP (N- methyl-2-pyrrolidone), dichloromethane or THF.
  • the preferred solvent is DMF.
  • the solvent used for extraction of the compound of formula XIII as obtained in step (iii) is selected from THF or dichloromethane.
  • the preferred solvent is dichloromethane.
  • the solvent used in step (iv) is an alcohol selected from methanol, ethanol, isopropanol, n-propanol, n-butanol t-butanol, 2-butanol or isobutanol
  • the preferred solvent is isopropanol.
  • step (v) The purification of compound of formula XIV as obtained in step (v) is carried out with methyl ethyl ketone which yields a compound having an HPLC purity of 90 % a/a.
  • the dealkylating agent used in step (v) for the dealkylation of the compound of formula (XIV) is selected from pyridine hydrochloride, boron tribromide, boron trifluoride etherate, anhydrous aluminium chloride, iodocyclohexane, aqueous HBr (hydrobromic acid), L-methionine, a mixture of thiourea and anhydrous aluminium chloride or 2- (diethylamino)ethane thiol hydrochloride.
  • the preferred dealkylating agent is pyridine hydrochloride.
  • step (vi) involving preparation of hydrochloride salt of the compound of formula (1 ) is carried out using hydrochloride gas dissolved in isopropyl alcohol (IPA.HCI) in the presence of a solvent selected from methanol, ethanol, isopropanol, diethyl ether, diisopropyl ether or a combination thereof.
  • IPA.HCI isopropyl alcohol
  • the solvent used in step (vi) is a mixture of methanol and diisopropyl ether.
  • the purity of compound of formula (1 ) obtained by this process is 97 % a/a.
  • the compound of formula (1 ) which is prepared from the key intermediate include: (+)-irans-2-(2- chlorophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4- one or its hydrochloride and (+)-frans-2-(2-Chloro-4-trifluoromethyl-phenyl)-5,7- dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one or its hydrochloride.
  • CDK Cyclin-dependent kinases
  • CDCI 3 Deuterated chloroform
  • reaction mixture was washed with 1 L of toluene, aqueous layer was separated and adjusted the pH to 1 1 - 12 using 1 L of 50 % sodium hydroxide solution at 5 - 10 °C to precipitate out the solid.
  • the resulting solid was filtered and dried under vacuum (NLT 650 mm of Hg) at 50 - 60 °C until moisture content was not more than 0.5 %.
  • the reaction mixture was slowly heated to 50 - 55 °C and maintained at 50 - 55 °C for 1 h.
  • the resulting mixture was gradually cooled to 20 - 25 °C, 687.6 mL of 50 % sodium hydroxide solution (pH should be 9 - 10) and 247.5 mL of 50 % hydrogen peroxide solution were added by maintaining the temperature of the reaction mixture at 20 - 25 °C.
  • the reaction mixture was slowly heated to 50 - 55 °C and maintained at 50 - 55 °C for 1 h. After completion of reaction, 550 mL of cold water (15 - 20 °C) was charged and filtered through celite bed.
  • the main filtrate was collected and the bed was washed with 3 x 550 mL ethyl acetate and stored the filtrate (ethyl acetate) in a separate container.
  • the organic layer was separated from the main filtrate and washed the aqueous layer with the filtrate (ethyl acetate) collected in a separate container.
  • the organic layers were combined and washed with 550 mL of 10 % brine solution.
  • the organic layer was distilled out (THF and ethyl acetate) under vacuum at 40 - 45 °C and chased with 550 mL of ethyl acetate repeatedly till THF content in distillate by GC should be less than 0.5 %.
  • the aqueous layer was separated and further extracted with ethyl acetate.
  • the combined organic layer was separated and dried over anhydrous sodium sulfate.
  • the organic layer was distilled out completely under vacuum (NLT 650 mm of Hg) at 40 - 45 °C to yield a viscous liquid.
  • the mixture was cooled to 20 - 25 °C and the layers were allowed to settle down.
  • the upper isopropyl alcohol was separated and diluted with thrice the volume of isopropyl alcohol layer using ice cold water.
  • the resulting solution was extracted with thrice the volume of isopropyl alcohol layer using ethyl acetate, organic layer was separated and the extraction of aqueous layer was carried out using the same volume of ethyl acetate as above.
  • the organic layers were combined and washed with thrice the volume of isopropyl alcohol layer using brine solution.
  • the organic layer was separated and dried over sodium sulfate.
  • the organic layer was evaporated under vacuum at 45 - 50 °C to reduce the volume to 20 % (visual) to get a viscous liquid and extracted the viscous liquid with seven times the volume of the viscous liquid using diisopropyl ether at 60 - 65 °C. The extractions were repeated using thrice the volume of the viscous liquid using diisopropyl ether at 60 - 65 °C.
  • the total organic layers were combined, evaporated under vacuum at 45 - 50 °C to reduce the volume to about 10 %, cooled to 5 - 10 °C and the precipitated solid was filtered.
  • the bed was washed with 220 mL hexane, dried under vacuum (NLT 650 mm of Hg) at 35 - 40 °C for 10 - 12 h to yield a pale yellow solid.
  • the seeding material was added at 43 - 45 °C, gradually cooled the mixture to 38 - 40 °C over a period of 1 h and maintained at 38 - 40 °C for 2 h.
  • the reaction mixture was further cooled to 20 - 25 °C over a period of 1 .0 - 1 .5 h, the precipitated solid was centrifuged and the bed was washed with 15 mL of chilled methanol.
  • dichloromethane was distilled completely under vacuum below 40 °C, chased with 25 mL of diisopropyl ether under vacuum below 40 °C and distilled under vacuum to remove the traces of solvent below 40 °C to yield yellow residue. Yield: 55 g, quantitative.
  • the mixture was cooled to 0 - 5 °C and quenched into 1250 mL of ice-cold water below 5 °C to which 150 mL of 33 % sodium carbonate solution was added over a period of 3 - 4 h by maintaining the temperature between 0 - 5 °C until pH was maintained at 8 to 9.
  • the reaction mixture was extracted with 2 x 200 mL of dicholoromethane, the organic layer was separated and washed with 2 x 165 mL of 10 % sodium chloride solution. The organic layer was dried over 5 g of anhydrous sodium sulfate and distilled under vacuum below 45 °C. The residue was dried under vacuum (NLT 650 mm of Hg) for 2 - 3 h to yield viscous liquid.
  • the reaction mixture was quenched with 249.6 mL of ice-cold water, the organic layer was separated and the aqueous layer was extracted with 49.4 mL of methylene dichloride.
  • the combined organic layer was washed with 124.8 mL of 6 % sodium bicarbonate solution followed by 247 mL of 10 % sodium chloride solution.
  • the organic layer was separated, dried over 13 g of anhydrous sodium sulphate and distilled out the solvent from the organic layer below 40 °C under vacuum completely to yield residue.
  • the reaction mixture was extracted with 2 x 455 mL of methylene dichloride, separated the organic layer and washed the combined organic layer with 2 x 455 mL of 10 % of sodium chloride solution.
  • the organic layer was separated, dried over 200 g of anhydrous sodium sulphate and distilled out the solvent from the organic layer below 40 °C under vacuum to yield a viscous liquid.
  • 364 mL of isopropyl alcohol-HCI was added at 10 - 15 °C, slowly allowed to 25 - 30 °C and maintained for 10 - 16 h. After completion of the reaction, distilled out IPA below 45 °C under vacuum and diluted the reaction mixture with 910 mL of ice cold water.
  • the resulting mixture was cooled to 10 - 15 °C and basified to pH 9 -10 using 273 mL saturated sodium carbonate solution.
  • the reaction mixture was extracted with 2 x 455 mL of methylene dichloride and the organic layer was washed with 2 x 455 mL of 10 % sodium chloride solution.
  • the organic layer was separated, dried over 45.5 g of anhydrous sodium sulphate and the solvent was distilled out completely below 40 °C under vacuum to yield a residue.
  • reaction mixture was further cooled to 0 - 5 °C, filtered and the bed was washed with 36 mL methyl ethyl ketone followed by 90.7 mL hexane to yield a wet cake.
  • the wet compound was dried under vacuum below 50 °C to yield a dry solid.
  • 35 g of compound of example 8 and 38.5 g of pyridine hydrochloride were heated to 135 - 140 °C, maintained for 60 min and pyridine was simultaneously distilled out until temperature of 175 - 180 °C was attained.
  • the reaction mixture was further maintained at 175 - 180 °C over a period of 5 - 8 h.
  • the reaction mixture was cooled to 65 - 70 °C, the reaction mixture was dissolved in 35 mL of methanol and quenched with 15 % sodium carbonate solution (350 mL) at 25 - 30 °C under stirring.

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Abstract

La présente invention concerne un procédé de préparation d'un intermédiaire clé (tel que décrit dans la présente invention) utilisé dans la synthèse d'énantiomères (+)-trans de flavones substituées par une pyrrolidine, représenté par la formule (1) ou des sels pharmaceutiquement acceptables de ceux-ci ; lesquels sont des inhibiteurs des kinases cycline-dépendantes (CDK) et peuvent être utilisés pour le traitement de troubles prolifératifs tels que le cancer. Dans la formule (1), R a la signification donnée dans les revendications. Le procédé selon la présente invention présente les avantages d'un rendement et d'une pureté supérieurs, d'une température de réaction réduite, est cohérent et implique l'utilisation de solvants non toxiques. Le procédé selon la présente invention permet une synthèse efficace à grande échelle, et la pureté du produit obtenu est supérieure à 97 %.
PCT/IB2013/051331 2013-02-19 2013-02-19 Procédé de préparation d'un intermédiaire de flavones substituées par une pyrrolidine Ceased WO2014128523A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11007174B2 (en) 2013-07-12 2021-05-18 Piramal Enterprises Limited Pharmaceutical combination for the treatment of melanoma

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148158A1 (fr) * 2006-06-21 2007-12-27 Piramal Life Sciences Limited Dérivés de flavone enantiomériquement purs pour le traitement de troubles polifératifs et leurs procédés de préparation

Patent Citations (1)

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WO2007148158A1 (fr) * 2006-06-21 2007-12-27 Piramal Life Sciences Limited Dérivés de flavone enantiomériquement purs pour le traitement de troubles polifératifs et leurs procédés de préparation

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US11007174B2 (en) 2013-07-12 2021-05-18 Piramal Enterprises Limited Pharmaceutical combination for the treatment of melanoma
US11839591B2 (en) 2013-07-12 2023-12-12 Piramal Enterprises Limited Pharmaceutical combination for the treatment of melanoma
US12383530B2 (en) 2013-07-12 2025-08-12 Piramal Enterprises Limited Pharmaceutical combination for the treatment of melanoma

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