Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention mainly relates to the process for preparation of Apixaban (formula-I) or pharmaceutically accepted salts or solvates or hydrate form.
• This instant invention further relates to process for preparation of Apixaban intermediates, namely ethyl 6-(4-iodophenyl)- l -(4-methoxyphenyI)-7-oxo-4,5,6,7-tetrahydro- l H- pyrazolo[3,4-c]pyridine-3-carboxylate (Formula- D) and 6-(4-pyridinone)-l -(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro- l H-pyrazolo[3,4-c]pyridine-3-carboxylate (Formula- E).
• the formula (I), formula (D) and formula (E) are structurally represented as below;
• Apixaban is chemically known as 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo-l-piperidiny
• Apixaban is highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa (fXa), was developed in a late-stage clinic trial for the prevention and treatment of thromboembolic diseases by Bristol-Myers Squibb. [Thromb. Haemost. 2010, 104, 301 -3 10 and J. cardiovasc. Pharm. 2010, 55, 609-616] It could be marketed for the treatment of deep vein thrombosis (DVT) and venous thrombosis as a new-generation anticoagulant. [J. Thromb. Haemost. 2008, 6, 1313— 13 1 8] Moreover, it has also shown promise in treating acute coronary syndrome (ACS), [Thromb. Haemost. 2010, 104, 976-983] cerebrovascular ischemia, and cancer. [Arterioscler. Thromb. Vase. Biol. 2007, 27, 1238-1247].
• ACS acute coronary syndrome
• Apixaban firstly disclosed in US 6,967,208 wherein, Apixaban has indicated first as its requirement for the use as an antithrombotic agent and thus being developed for oral administration.
• WO-2010/030983 disclosed a similar pathway for synthesis of formula [I], as described in scheme-1 , with marginal increase in yield of the Ullmann reaction -29% yield is reported.
• WO-2012/ 168364 discloses the preparation of formula(E), (Ullmann coupling reaction) by using the base as 3 PO 4 and N'N' dimethyl ethylenediamine in toluene as a solvent with slight improved in yield up to 67%, after the crystallization of crude in ethyl acetate.
• WO2003/049681 discloses alternate methodology, which underwent an Ullmann coupling with iodide in the presence of cuprous iodide to obtained intermediate(C), in 68% yield.
• the Same instant application also teaches the requirement of expensive organic cuprous compound Cu(PPh ) 3 Br as catalyst for the Ullmann coupling reaction in order to enhanced yield up to 68%.
• the present invention is to provide the novel process for preparation of compound formula (D), by treating compound formula (A), with compound formula (B), in polar protic or aprotic solvents in presence of base to obtained formula (c), which concomitantly treated with suitable acid in polar solvent to obtained formula (D).
• the present invention is to provide the novel process for preparation of compound formula (E), wherein intermediate formula (D), is treated with valerolactum in aprotic solvents in presence of suitable base, ligand and catalyst to exert intermediate formula (E).
• present invention is to provide the novel process for preparation of Apixaban of compound formula (I), by amidation of compound formula (E), with suitable aminating agent in polar solvent or without polar solvent.
• present invention is to provide the compound formula (I); Apixaban which is substantially free from the impurity of compound formula (F), by dissolving Apixaban in suitable solvent and extracted with carbonate water solution.
• present invention is to provide the compound formula (I); Apixaban which is substantially free from the impurity of compound formula (G), by crystallizing the formula (I), with suitable polar solvents mixture.
• the main aspect of the present invention is to introduced novel process for the preparation of intermediate (D) & intermediate (E), and process for Apixaban formula (I). Further the present invention introduced the novel reaction combi-pack for Ullmann coupling which accountable to enhance the yield of formula (E), and concomitantly exert Apixaban of formula [I].
• the present invention provides an novel process for preparing an intermediate (D), wherein reacting intermediate (A), and intermediate (B), in presence of organic base selected from triethylamine (TEA), Diisopropyl ethyalamine and in protic polar or aprotic non polar solvents selected from methanol,ethanol,iso- Propanol,n-propanol,iso-amyl alcohol, butanol and toluene or mixture thereof to form cycloaddition product of an intermediate formula(C).
• organic base selected from triethylamine (TEA), Diisopropyl ethyalamine and in protic polar or aprotic non polar solvents selected from methanol,ethanol,iso- Propanol,n-propanol,iso-amyl alcohol, butanol and toluene or mixture thereof to form cycloaddition product of an intermediate formula(C).
• Intermediate(C) is further in situ reacted with acid such as trifluoroacetic acid (TFA), acetic acid, sulphuric acid, and Hydrochloric acid or mixture thereof in polar protic solvents selected from methanol, ethanol iso-Propanol, n-propanol, iso-amyl alcohol and butanol or mixture thereof to obtain intermediate(D), in pure state and high yield without any further purification.
• acid such as trifluoroacetic acid (TFA), acetic acid, sulphuric acid, and Hydrochloric acid or mixture thereof in polar protic solvents selected from methanol, ethanol iso-Propanol, n-propanol, iso-amyl alcohol and butanol or mixture thereof to obtain intermediate(D), in pure state and high yield without any further purification.
• acid such as trifluoroacetic acid (TFA), acetic acid, sulphuric acid, and Hydrochloric acid or mixture thereof in polar protic
• the solvent used for the preparation of intermediate (D) is preferably a methanol as methanol exert the good yield and the after completion of reaction solid come up in the same reaction mass without addition of any solvent and without any work up of reaction.
• the obtained solid having the good purity without any further purification.
• methanol is used as a solvent for reaction and isolation as well by avoiding the number of solvents usage and without work up of reaction which concomitantly exert environment friendly with economic significance.
• the present invention provides an novel process for preparing an intermediate (E), wherein reacting intermediate (D), with piperidine-2- one (valarolactum) in toluene as a solvent and in presence of base selected from cesium carbonate,potassium carbonate and potassium terbutoxide with iigand precursor selected from dimethylaniline (DMA), Dimethyl aminopyridine(DMAP) and 8-hyrdoxyquinoline, with catalytic amount of cuprous iodide (Cul) to obtain intermediate (E), in pure form with high yield without any further purification (yield -85-90%).
• the unique or selective combination of reaction pack is cesium carbonate as a base, dimethylaniline (DMA) as ligand precursor and catalyst Cul which are mainly accountable for enhancement in yield without undergoing any side reactions.
• the present invention provides a process for preparing Apixaban [I], by amidation reaction using aqueous
• ammonia or mixture of aqueous ammonia in polar protic solvents selected from methanol, ethanol, isopropanol, n-propanol, iso-amyl alcohol and butanol or mixture thereof at 65-70°C for 4-8, hours to obtain apixaban containing acid impurity of formula (F) in ⁇ 1 -2%.
• the obtained Apixaban with acid impurity is dissolved water immiscible solvents selected from ethyl acetate, methylene dichloride and ethylene dichloride or mixture thereof and washed with 2-5% sodium bicarbonate solution further evaporated the water immiscible solvents under reduced pressure followed by crystallization in mixture of methanol-water to obtain pure Apixaban [I] without any further purification with high yield and purity as per the ICH guideline.
• water immiscible solvents selected from ethyl acetate, methylene dichloride and ethylene dichloride or mixture thereof
• Example-2 Synthesis of compound of formula D: ethyl 6-(4-iodophenyl)-l-(4- methoxyphenyl)-7-oxo-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3, 4-c] pyridine-3- carboxylate
• Example-3 Synthesis of compound of formula D: ethyl 6-(4-iodophenyl)-l-(4- methoxyphenyl)-7-oxo-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3, 4-c] pyridine-3- carboxylate
• ExampIe-4 Synthesis of compound of formula E: l-(4-methoxyphenyl)-7-oxo (4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine carboxalic acid ethyl ester.
• Example-5 Synthesis of compound of formula E: l-(4-methoxyphenyl)-7-oxo-6- (4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3- carboxalic acid ethyl ester.
• MDC methylene dichloride
• Example 8 Synthesis of compound of formula [I] : 4, 5, 6, 7-tetrahydro-l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl) phenyl]-lH-pyrazolo [3, 4-c] pyridine-3-carboxamide (Crude Apixaban).
• Example-9 Synthesis of compound of formula [I]: 4, 5, 6, 7-tetrahydro-l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxo-I-piperidinyI) phenyl]-! H-pyrazolo [3, 4-c] pyridine-3-carboxamide (Apixaban).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 2015
  • 2015-01-06 EP EP15723309.9A patent/EP3097100A2/en not_active Withdrawn
  • 2015-01-06 IN IN197MU2014 patent/IN2014MU00197A/en unknown
  • 2015-01-06 US US15/113,430 patent/US20170008886A1/en not_active Abandoned
  • 2015-01-06 WO PCT/IN2015/000007 patent/WO2015111073A2/en not_active Ceased

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