Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to processes to prepare an optically pure pharmaceutical active compound, particularly the compound zolmitriptan.
• Zolmitriptan is known as (4S)-4-[3-(2-dimethyi amino ethyl)-1H-5-indolyl methyl]- 1 ,3-oxazolan-2-one, or (S)-4-[[3-[2-(dimethylamino)ethyl]-1 H-indol-5-yl]methyl]-2- oxazolidinone, has the formula C 1 6H2 1 N 3 O 2 and a molecular weight of 287.36, and is represented by structure (I):
• the present invention also relates to a process of purification of optically pure zolmitriptan.
• Zolmitriptan is a dual action 5-HT 1B/1 D receptor agonist that is used as a therapeutic agent for treating migraine.
• Nasal spray and tablet products containing the drug are sold using the trademark ZOMIG.
• Earlier disclosures for the preparation of optically pure zolmitriptan have disadvantages, particularly for scale-up to produce commercial quantities.
• a first aspect of the present invention comprises a process for the preparation of zolmitriptan by the steps: (a) forming a diazo salt having formula (IV) from (4S)-4-(4- aminobenzyl)-1 ,3-oxazolan-2-one, (IV) where X represents a halogen; (b) forming an enol derivative having formula (V) from alkyl-2-acetyl-5- (1 ,3-dioxo-2,3-dihydro-1/7-2-isoindolyl) pentanoate, where R represents a straight or branched chain C 1 -C4 alkyl group and M represents an alkali metal; (c) coupling diazo salt (IV) and enol derivative (V) to form a hydrazone having formula (VI)
• R represents a straight or branched chain C 1 -C 4 alkyl group; (f) N,N-dimethylating primary amine (VIII) to form a tertiary amine having formula (IX),
• a second aspect of the present invention comprises a process for the preparation of zolmitriptan by the steps: (i) hydrolyzing an an indole derivative having formula (VII),
• zolmitriptan N,N-dimethylating the oxazolan-2-one (XII) to form zolmitriptan.
• Another aspect of the present invention is providing non solvated, pure zolmitriptan.
• the present invention provides compounds having the following structures (VI), (VII), (VIII), (X) and (XI).
• the invention provides processes for the preparation of compounds having the structures (VI) to (XI). BRIEF DESCRIPTION OF THE DRAWING
• Fig. 1 is a diagram of a process scheme for preparing zolmitriptan. DETAILED DESCRIPTION
• a first aspect of present invention includes a process for the preparation of zolmitriptan with reference to the scheme shown in Fig. 1 , comprising the steps of: (a) diazotizing (4S)-4-(4-aminobenzyl)-1 ,3-oxazolan-2-one (described in U.S.
• R represents a C 1 -C4 alkyl group of either a straight or branched chain; then (2) N,N-dimethylating the primary amine (VIII) to synthesize the tertiary amine of the formula (IX) where R represents C ⁇ -C 4 alkyl group of either straight or branched chain; and. (3) treating the ester (IX) with an aqueous solution of a mild base such as sodium carbonate or potassium carbonate followed by treating with a strong acid such as concentrated HCI, to give zolmitriptan (I).
• a mild base such as sodium carbonate or potassium carbonate
• a strong acid such as concentrated HCI
• the process to form zolmitriptan comprises, in sequence: (1a) hydrolyzing the ester group of the indole derivative of the formula (VII) to the corresponding carboxylic acid of the formula (X)
• This compound (VI) can optionally be converted in situ to the indole derivative alkyl-3-[2-(1 ,3-dioxo-2,3,3a,7a-tetrahydro-1 H-2-isoindolyl)ethyl]-5-[(4S)- 2-oxo-l ,3-oxazolan-4-yl methyl]-1 H-2-indole carboxylate of the formula (VII), through an acid catalyzed 3,3-sigmatropic shift in a moisture controlled medium.
• This cyclization step can be carried out in an alcoholic medium such as
• the alkyl group R of compounds (VI), (VII), (VIII), and (IX) can be a single group like methyl, ethyl, isopropyl, etc. or may be a mixture of such groups depending on the R group in compound (III) and the alkyl group of the alcohol in the alcoholic solution used as the medium, as well as the reagent used for cyclization of the hydrazone intermediate (VI).
• the mutual ratio between the two esters can vary and is not important, due to the final decarboxylation to afford the zolmitriptan compound (I).
• the ratio of the two alkyl groups in all of intermediates (VI), (VII), (VIII), and (IX). will be between 5:95 and 95:5, or between 10:90 and 90:10.
• Step (1) prepares compound (VIII) by the Ing-Manaske reaction where phthalimide is deprotected using base such as an N-containing base like hydrazine or alkylamines (RNH 2 ).
• the formed amine of the formula (VIII) can be isolated both in the free amine form as well as in the corresponding salt form. Maintaining the intermediate, in its salt form is preferable from a process point of view, as compound (VIII) tends to cyclize to form the cyclized amide of formula (XIII) after a prolonged maintenance in a basic medium:
• Step (2) is an Esweiler-Clark methylation of intermediate (VIII) to prepare the compound of formula (IX). Due to the complex nature of compound (IX), a comparatively low-temperature reaction is chosen where a metal hydride (e.g., sodium, cyanoborohydride, or sodium borohydride) is employed as the hydrogen donor while maintaining the pH in a mildly acidic region, such as using acetic acid buffer systems. It was found that the reaction yields an impure reaction mass when formic acid was chosen as the hydrogen donor and the reaction was carried out at an elevated temperature (>150°C).
• a metal hydride e.g., sodium, cyanoborohydride, or sodium borohydride
• Step (3) is a one-pot reaction wherein the intermediate (IX) is first treated with a non-hydroxyl base in an aqueous medium, followed by the treatment with strong aqueous acid to afford zolmitriptan of the formula (I).
• a relatively milder base such as sodium carbonate or potassium carbonate
• zolmitriptan can be prepared from intermediate (VII) following the sequence of steps (1 ), (2), and (3) without isolating the intermediate (IX).
• the intermediate (X) and the decarboxylated intermediate (XI) optionally may not be isolated after they are formed.
• the in situ intermediate (XI) is then subjected to deprotection of its phthalamide moiety in step (3a) to prepare compound of formula (XII). N,N-dimethylation of compound of formula (XII) in step (4a) affords the zomitriptan product.
• a process for the purification of optically pure (4S)-4-[3-(2-dimethyl amino ethyl)-1H-5-indolyl methyl]-1 ,3-oxazolan-2-one which comprises: (i) dissolving the crude (4S)-4-[3-(2-dimethyl amino ethyl)-1 H-5-indolyl methyl]-1 ,3-oxazolan-2-one (I) in isopropyl alcohol at an elevated temperature and filtering the hot solution under positive pressure, (ii) slowly cooling the filtrate to a temperature of 20-30°C.
• the preferable quantity of isopropanol in the step (i) is three times weight- to-volume ratio against the crude compound having a purity of 95-99%.
• the hot solution can be decolorized using decolorizing charcoal prior to the filtration or centrifugation.
• the preferable quantity of n-heptane in the step (iii) is a weight-to-volume ratio of one, versus the crude compound of purity 95-99%.
• a mixture of isopropyl alcohol and n-heptane can be used for complete transfer of the solid to the filtration bed a mixture of isopropyl alcohol and n-heptane can be used.
• the preferable composition is a 50:50 mixture, cooled to 10-15°C before use.
• the drying stage of step (vi) can be carried out at an elevated but non- extreme temperature under vacuum.
• the present invention provides non-solvated, pure (4S)- 4-[3-(2-di methyl amino ethyl)-1H-5-indolyl methyl]-1 ,3-oxazolan-2-one.
• the present invention provides compounds of the following formulae (VI), (VII), (VIII), (X), and (XI).
• the invention provides processes for the preparation of compounds (IV) to (XII).
• compounds (IV) to (VI) see process steps (a), (b), and (c) that were previously described.
• process step (d) see process step (1) as previously described.
• compound (IX) see process step (2) as previously described.
• the preparation of compound (X) is shown by process step (1a) described above.
• Compound (XI) is prepared by process step (2a) in the prior description.
• For the preparation of compound (XII) see step (3a) in the prior description.
• Example 1 EthyI-3-[2-(1 ,3-dioxo-2,3-dihydro-1 H-2-isoindoleyl)ethyl]- 5-[(4S)-2-oxo-1 ,3-oxazolan-4-ylmethyl]-1 H-2-indole carboxylate (VII)
• Part B In a separate vessel, ethyl-2-acetyl-5-(1 ,3-dioxo-2,3-dihydro-1H-2- isoindolyl) pentanoate of the formula (III) (346.4 g, 1.09 moles) was added to methanol (3400 ml), sodium acetate (340 g, 4.15 moles) was added, and the mixture was stirred at room temperature for one hour. After cooling to 0-5° C the Part A solution was added slowly. Following the addition, the mixture was stirred for 2-3 hours at room temperature. Progress of the reaction was monitored by TLC using ethyl acetate as the mobile phase. The reaction mass was extracted with dichloromethane (2.5 L x 3 times).
• the combined dichloromethane layer was washed with water (1.25 L x 2 times), dried and concentrated to produce a crude residue containing the hydrazone intermediate, and this residue was used for cyclization to form the indole moiety.
• the hydrazone intermediate had the following properties: 1 H NMR: (DMSO-d 6 , 200 MHz): ⁇ 1.26 (t, 3H), 1.64-1.92 (m, 4H), 2.15-2.44
• Example 2 Ethyl 3-(2-aminoethyl)-5-[(4S)-2-oxo-1,3-oxazolan-4- ylmethyl]-1H-2 -indole carboxylate : hydrochloride salt (VIII) Ethyl-3-[2-(1 ,3-dioxo-2,3-dihydro-1 H-2-isoindoleyl)ethyl]-5-[(4S)-2-oxo-1 ,3- oxazolan-4-ylmethyl]-1H-2-indole carboxylate of the formula (VII) (100 g, 0.217 moles) was dissolved in 800 ml of methanol at room temperature with stirring, then 42.17 ml (43.4 g, 0.867 moles) of hydrazine hydrate were added dropwise over about 20-30 minutes, with stirring at 35-40°C.
• VIII Ethyl 3-(2-aminoethyl)-5-[(4
• the mixture was maintained under stirring at the same temperature for 150 minutes, and analyzed by TLC using ethyl acetate as the mobile phase to show completion of the reaction.
• the reaction mass was cooled to 10-15°C and 950 ml of 2N HCI were added to it in a dropwise manner.
• the mass was diluted with 550 ml of water, evaporated to remove methanol, and cooled to 10- 15°C.
• the solid was removed by filtration.
• the filtrate was concentrated to a 350-400 ml volume, cooled to 10-15°C and 1000 ml dichloromethane were added, and stirring was continued for 15 minutes at 10- 15°C.
• Example 3 Ethyl 3-(2-dimethyl aminoethyl)-5-[(4S)-2-oxo-1,3- oxazolan-4-yl methyl]-1H-2 -indole carboxylate : Hydrochloride salt (IX) 100 g (0.27 moles) of ethyl 3-(2-aminoethyl)-5-[(4S)-2-oxo-1 ,3-oxazolan-4- ylmethyl]-1/-/-2-indole carboxylate hydrochloride salt (VIII) were dissolved in 1334 ml of methanol at room temperature under stirring, neutralized to pH 7 by adding 20% sodium carbonate solution dropwise, and 39.92 ml (40.8 g, 0.68 moles) of glacial acetic acid were added to it at the same temperature.
• Hydrochloride salt (IX) 100 g (0.27 moles) of ethyl 3-(2-aminoethyl)-5-[(4
• reaction mass was cooled to 10-15°C.
• Sodium cyanoborohydride (42.16 g, 0.68 moles) is added pinch by pinch to the reaction mixture with stirring at this temperature.
• the mixture was cooled to -5° to 0°C.
• a mixture of 209.2 ml of 38% aqueous formaldehyde solution (81.6 g, 2.72 moles) and 666 ml methanol was added to the reaction mixture in a dropwise fashion at -5 to 0°C, with stirring. Stirring was continued at the same temperature for another 60-90 minutes and then reaction progess was monitored by TLC using 30% methanol and 1.5% NH 3 in dichloromethane as the mobile phase. TLC showed the completion of reaction as the starting material disappeared.
• reaction mixture was gently heated to reflux and monitored by TLC using 30% Methanol in dichloromethane as the mobile phase. After 2-2.5 hours of reflux, TLC showed a completion of reaction since the starting material vanished. Heating was discontinued and the mixture was allowed to cool to 15-18°C. A hydrolysis sample was kept for TLC monitoring and to the mixture 150 ml of cone. (35%) hydrochloric acid was added dropwise. The mixture was then heated to reflux and monitored by TLC using 30% Methanol and 1.5% NH 3 in dichloromethane. After 3hrs of reflux TLC indicated completion. The reaction mixture was cooled to 20-25°C and extracted with 500 ml of ethyl acetate. The organic layer was discarded and the aqueous layer was further cooled to 15-20°C.
• 1,3-oxazolan-2-one (via in situ intermediate IX) 25 g (0.068 moles) of ethyl 3-(2-aminoethyl)-5-[(4S)-2-oxo-1 ,3-oxazolan-4- ylmethyl]-1H-2-indole carboxylate hydrochloride salt (VIII) was dissolved in 250 ml methanol at room temperature with stirring, neutralized to pH 7 by adding 20% sodium carbonate solution dropwise, and 9.37 ml (10.2 g, 0.17 moles) of glacial acetic acid were added at the same temperature. The reaction mass was cooled to 10-15°C.
• reaction mass was extracted with ethyl acetate (500 ml x 3 times) at 25-30°C. and all ethyl acetate layers were mixed and washed with water (50 ml x 2 times) and evaporated to dryness to yield 12.5 g residue.
• ethyl acetate 500 ml x 3 times
• water 50 ml x 2 times
• evaporated to dryness 12.5 g residue.
• To the solid residue 37.5 ml of isopropyl alcohol was added and slowly heated to reflux to result in a clear solution. After slowly cooling to 20-30°C, 12.5 ml of n-heptane were added dropwise. The mixture was stirred for 15-20 minutes and then filtered.
• Example 6 Purification of (4S)-4-[3-(2-dimethyl amino ethyl)-1H-5- indolyl methyl]-1,3-oxazolan-2-one (I) To a crude ziprasidone product (8.8 g) 26.4 ml of isopropyl alcohol were added and slowly heated to reflux to result in a clear solution. The clear solution was treated with 1 g of decolorizing charcoal at refluxing conditions for 10-15 minutes and then filtered under a positive pressure while hot. The clear filtrate was then slowly cooled to 20-30°C and 8.8 ml of n-heptane were added dropwise. Stirring continued for 15-20 minutes and the solution was filtered.
• Example 7 (4S)-4-[3-(2-aminoethyl)-1 H-5-indolylmethyl]-1 ,3-oxazolan- 2-one (XII)
• a solution of potassium carbonate (4.66 g, 0.033 mole) in water (20 ml) was added to 3.9 g (0.0084 mole) ethyl-3-[2-(1 ,3-dioxo-2,3-dihydro-1 H-2- isoindoleyl)ethyl]-5-[(4S)-2-oxo-1 ,3-oxazolan-4-ylmethyl]-1 H-2-indole carboxylate (VII) and the mixture was refluxed for 2 hours to obtain a clear solution.
• the intermediate (X) can be isolated using the procedure described in Example 12 or processed further as in the following procedure).
• the mixture was cooled to room temperature and concentrated HCI was added dropwise to pH 2; the mixture was refluxed for 5 hours.
• the mixture was extracted with ethyl acetate to remove organic impurities, the aqueous layer was adjusted with 20% NaOH solution to pH 10-11 and extracted with ethyl acetate.
• the ethyl acetate layer was dried over sodium sulfate and evaporated to dryness to yield a dark brown gummy crude mass that was used as such for further processing.
• Example 8 (4S)-4-[3-(2 -dimethyl amino ethyl)-1H-5-indolyl methyl]- 1 ,3-oxazolan-2-one (I)
• the crude mixture from Example 7 0.5 g, 0.0019 moles
• sodium cyanoborohydride 0.23 g, 0.0036 moles
• acetic acid 0.3 ml
• the mixture was adjusted with 10% potassium carbonate solution to pH 10-
• Part B In a separate vessel, ethyI-2-acetyl-5-(1 ,3-dioxo-2,3-dihydro-1H-2- isoindolyl) pentanoate of the formula (III) (86.64 g, 0.27 moles) was dissolved in methanol (860 ml) an sodium acetate (170.60 g, 2.08 moles) was added; the mixture was stirred at room temperature for one hour and cooled to 0-5° C. To this mixture was slowly added the Part A mixture. After the addition, the mixture was stirred for 2-3 hours at room temperature. Progress of the reaction was monitored by TLC using ethyl acetate as the mobile phase.
• the reaction mass was extracted with dichloromethane (250 ml x 3 times). The combined dichloromethane layer was washed with water (100 ml x 2 times), dried and concentrated.
• the crude residue (containing the hydrazone intermediate) was proceeded for cyclization to form the indole moiety.
• the above residue (210 g) was dissolved in 100 ml of ethanol, heated to form a transferable mass and, under refluxing conditions, 450 ml ethanolic HCI (18.0%) were added. The mixture was then further refluxed for 12 hours. The reaction mass was cooled to room temperature and the obtained solid was filtered, and washed with methanol.
• Example 10 Ethyl-3-[2-(1 ,3-dioxo-2,3-dihydro-1 H-2-isoindoleyl)ethyl]- 5-[(4S)-2-oxo-1 ,3-oxazolan-4-ylmethyl]-1 H-2-indole carboxylate (VII) Part A: (4S)-4-(4-aminobenzyl)-1 ,3-oxazolan-2-one of the formula (II) (10 g, 0.052 moles) was dissolved in methanol (30 ml) and water (45 ml) and cooled to 5-10° C, then concentrated HCI (13.6ml) was added dropwise to avoiding heating and the mixture was stirred for 10 minutes.
• Part B In a separate vessel, alkyl-2-acetyl-5-(1 ,3-dioxo-2,3-dihydro-1H-2- isoindolyl) pentanoate of the formula (III) (17.32 g, 0.0546 moles) was dissolved in methanol (170 ml), sodium acetate (17 g, 0.21 moles) was added and the mixture was stirred at room temperature for one hour, cooled to 0-5° C and the Part A mixture was added slowly. After the addition, the mixture was stirred for 2-3 hours at room temperature. Progress of the reaction was monitored by TLC, using ethyl acetate as the mobile phase.
• the reaction mass was extracted with dichloromethane (2.5 L x 3 times). The combined dichloromethane layer was washed with water (1.25 L x 2 times), dried, and concentrated.
• the crude residue (containing the hydrazone intermediate) was proceeded for cyclization to form the indole moiety.
• the above residue (30 g) was dissolved in 15ml methanol, heated to form a transferable mass and, under refluxing conditions, 60 L Isopropanol-HCI (12%) was added. The reaction mixture was further refluxed for 12 hours. The reaction mass was then cooled to room temperature and the produced solid was filtered and washed with methanol.
• Example 11 Ethyl 3-(2-dimethyl amino ethyl)-5-[(4S)-2-oxo-1,3-oxazolan-4-yl methyl]-1 H-2-indole carboxylate (IX) (via in situ intermediate VIII) Ethyl-3-[2-(1 ,3-dioxo-2,3-dihydro-1 H ⁇ 2-isoindoleyl)ethyl]-5-[(4S)-2-oxo-1 ,3- oxazolan-4-ylmethyl]-1 H-2-indole carboxylate of the formula (VII) (5 g, 10.85x10 "3 moles) was added to 40 ml methanol at room temperature with stirring.
• Example 12 3-[2-(1 ,3-dioxo-2,3,3a,7a-tetrahydro-1 H-2-isoindolyl)- ethyl]-5-[(4S)-2-oxo-1 ,3-oxazolan-4-ylmethyl]-1 r7-2-indolecarboxylic acid (X)
• X A solution of sodium carbonate (11.5 g, 0.1085 mole) in water (400 ml) was added to 50 g (0.1085 mole) ethyl-3-[2-(1,3-dioxo-2,3-dihydro-1H-2-isoindoleyl) ethyl]-5-[(4S)-2-oxo-1 ,3-oxazolan-4-ylmethyl]-1 H-2-indole carboxylate (VII) and the mixture was refluxed for 2 hours to obtain a clear solution.
• the mixture was acidified to pH 2 with concentrated HCI at 15-20°C and extracted with ethyl acetate vigorously. The ethyl acetate layer was washed with water to a neutral pH, dried over sodium sulfate, and evaporated completely to yield the crude product (40 g, 85%).
• 200 ml of xylene (LR grade) and 10 ml of glacial acetic acid were added and refluxed at 138-140°C for 15-17 hours. The mixture was then cooled and the free flowing solid was then filtered, washed with ethyl acetate to remove xylene, and dried.

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