WO2015083033A1 - An improved process for the preparation of fosaprepitant having improved purity - Google Patents

An improved process for the preparation of fosaprepitant having improved purity Download PDF

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Publication number
WO2015083033A1
WO2015083033A1 PCT/IB2014/066279 IB2014066279W WO2015083033A1 WO 2015083033 A1 WO2015083033 A1 WO 2015083033A1 IB 2014066279 W IB2014066279 W IB 2014066279W WO 2015083033 A1 WO2015083033 A1 WO 2015083033A1
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WIPO (PCT)
Prior art keywords
formula
compound
metal scavenger
pharmaceutically acceptable
acceptable salt
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Application number
PCT/IB2014/066279
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English (en)
French (fr)
Inventor
Dhileepkumar Krishnamurthy
Raghavendar Rao Morthala
Ashutosh JAGTAP
Prashant LADKAT
Ajay KUMBHAR
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Piramal Enterprises Limited
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Application filed by Piramal Enterprises Limited filed Critical Piramal Enterprises Limited
Publication of WO2015083033A1 publication Critical patent/WO2015083033A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to a process for the preparation of [3- ⁇ [(2R,35)-2-[(lR)- 1 - [3 ,5-bis(trifluoromethyl)phenyl]ethoxy] -3 -(4-fluorophenyl)morpholin-4-yl]methyl ⁇ -5- oxo- 2H-l,2,4-triazol-l-yl]phosphonic acid (Fosaprepitant or the compound of formula I) or its pharmaceutically acceptable salt, particularly bis(N-methyl-D-glucamine) salt; having improved purity, particularly having palladium (Pd) content less than 1 ppm.
  • Fosaprepitant is an anti-emetic drug, which is administered intravenously.
  • Fosaprepitant and its bis(N-methyl-D-glucamine) salt is approved for the treatment of chemotherapy induced nausea and vomiting and is available in the market by brand name EMEND® for injection in the US and IVEMEND® in the Europe.
  • the compound of formula I and its process of the preparation are disclosed in US Patent No. 5691336.
  • the ether extract is further dried over magnesium sulphate and evaporated to dryness to obtain dibenzyl ⁇ 3-[2( ?J-[(1 ?)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]-5-oxo-4,5- dihydro-[l,2,4]-triazol- l-yl]phosphonic acid (referred to as "the compound of formula ⁇ ”) in the form of an oily residue. To this oily residue, methanol is added to make a solution of the compound of formula II.
  • the reaction mass is then filtered through hyflo-bed. The filtrate is collected and distilled off under reduced pressure at 30-35°C to obtain solid. The obtained solid is then co-distilled with isopropyl alcohol and acetonitrile. To the reaction mass acetonitrile is added and the resulting reaction mass is stirred for 15 hours at room temperature. The reaction mass is then filtered and dried to yield bis(N-methyl-D-glucamine) salt of the compound of formula I having Pd content less than 3 ppm. This limit again exceeds the pharmacopeal limit of Pd content in injectable API which is required to be less than 1 ppm. The process described in said patent application does not provide the compound of formula I meeting this requirement of having Pd content less than 1 ppm. Hence, the compound of formula I obtained by using the process of the said patent application does not meet the requirement of pharmaceutical acceptable purity.
  • US Patent No. 7915407 describes a process for the preparation of the compound of formula I and its N-methyl-D-glucamine salt by catalytic hydrogenation of monobenzyl fosaprepitant with Pd catalyst in the presence of N-methyl-D-glucamine using methanol- water as a solvent. After completion of the reaction, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure to obtain the concentrated solution. To the concentrated solution, tri-n-butylphosphine is added as the metal scavenger at room temperature and the reaction mixture is stirred for 12 hours. The reaction mixture is further added to the mixture of methanol- acetonitrile to precipitate the solid.
  • the inventors of the present invention have been successful in providing the compound of formula I having Pd content less than 1 ppm through an improved process. Moreover, the improved process for the preparation of the compound of formula I provides the said compound in good yield and enhanced purity.
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphen
  • Yet another object of the present invention is to provide an improved process for producing the compound of formula I having Pd content less than 1 ppm with yield of 80% and purity of > 99.0% %.
  • an improved process for the preparation of the compound of formula I (Fosaprepitant) or the pharmaceutically acceptable salt thereof having palladium (Pd) content less than 1 ppm wherein said process comprises the steps of; a. catalytic hydrogenation of the compound of formula II with Pd catalyst optionally in the presence of a base, to provide the compound of formula I or the pharmaceutically acceptable salt thereof; b.
  • a metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger
  • an improved process for the preparation of the compound of formula I or the pharmaceutically acceptable salt thereof; having Pd content less than 1 ppm comprising treating the compound of formula I or the pharmaceutically acceptable salt thereof twice with a metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.
  • a metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or
  • the process of the present invention involves reducing Pd content in the compound of formula I or the pharmaceutically acceptable salt thereof to less than 1 ppm and the said process involves catalytic hydrogenation of the compound of formula II with a Pd catalyst optionally, in the presence of a base, to provide the compound of formula I or the pharmaceutically acceptable salt thereof, and which process involves optionally isolating the compound of formula I or the pharmaceutically acceptable salt thereof; and treating the compound of formula I or the pharmaceutically acceptable salt thereof; twice with the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal s
  • Formula I wherein said process comprises the steps of: a. catalytic hydrogenation of the compound of formula II with palladium (Pd) catalyst optionally, in the presence of a base, to provide the compound of formula I or a pharmaceutically acceptable salt thereof; b.
  • a metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphen
  • a base is used to obtain the pharmaceutically acceptable salt of the compound of formula I.
  • the base used in the step (a) of the process is selected from the group consisting of potassium bicarbonate, sodium bicarbonate and N- methyl D-glucamine.
  • step (a) of the process Pd catalyst is used in an amount ranging from 1% to 10% based on the compound of formula II.
  • the metal scavenger in the step (b) of the process, is used in an amount ranging from 10% to 30% based on the compound of formula II.
  • the metal scavenger used in step (b) of the process is smopex ® 234.
  • Smopex ® 234 a trade mark of Johnson Matthey, is a metal scavenger which is used to remove and recover various metals from aqueous and organic solutions.
  • Smopex ® 234 mercaptoethylacrylate is grafted onto fibres.
  • the metal scavenger used in step (b) of the process is selected from the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger.
  • the siliabond metal scavenger is selected from the group consisting of siliabond thiol, siliabond thiourea, and siliabond amine and siliabond diamine.
  • the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with metal scavenger such that two different metal scavengers are used. Accordingly, in an embodiment the compound of formula I or the pharmaceutically acceptable salt thereof is treated with TPP as the first metal scavenger followed by treatment with smopex ® 234 as the second metal scavenger. In another embodiment of the invention, the compound of formula I or the pharmaceutically acceptable salt thereof is treated with smopex ® 234 as the first metal scavenger followed by treatment with TPP as the second metal scavenger.
  • a process for the preparation of the compound of formula I or the pharmaceutically acceptable salt thereof; having Pd content less than 1 ppm comprising treating the compound of formula I or the pharmaceutically acceptable salt thereof with a metal scavenger; wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex ® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.
  • a metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), a mixture of
  • the metal scavenger used is in an amount ranging from 10% to 30% based on the compound of formula II.
  • the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with smopex ® 234 as the metal scavenger.
  • the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with a metal scavenger selected from the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger.
  • a metal scavenger selected from the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger.
  • siliabond metal scavenger is selected from the group consisting of siliabond thiol, siliabond thiourea, siliabond amine or siliabond diamine.
  • the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with metal scavenger such that two different metal scavengers are used. Accordingly, in an embodiment, the compound of formula I or the pharmaceutically acceptable salt thereof is treated with TPP as the first metal scavenger followed by treatment with smopex ® 234 as the second metal scavenger. In another embodiment of the second aspect of the present invention, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated with smopex ® 234 as the first metal scavenger followed by treatment with TPP as the second metal scavenger.
  • the compound of formula I or the pharmaceutically acceptable salt thereof obtained by using the process of the present invention is of pharmaceutically acceptable purity with Pd content less than 1 ppm.
  • the compound of formula II used as a starting material in step (a) of the above process, is a known compound.
  • the compound of Formula II can be obtained by following the methods known in the literature. For example, the process described in the US patent no. 5,691,336 (the US '336 Patent) can be used to obtain the compound of formula II.
  • reaction mixture was quenched with saturated aqueous sodium bicarbonate solution.
  • the quenched reaction mixture was extracted with ethyl ether.
  • the ethyl ether extract was then washed with aqueous potassium bisulphate solution followed by saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution and further, dried over magnesium sulphate.
  • the ethyl ether extract was then evaporated to dryness to obtain the compound of formula II.
  • the process for obtaining the compound of formula I or the pharmaceutically acceptable salt thereof; having Pd content less than 1 ppm involves hydrogenating the compound of formula II with Pd catalyst in an organic solvent optionally, in the presence of a base at 35-50°C to obtain the compound of formula I or the pharmaceutically acceptable salt thereof.
  • the compound of formula I or the pharmaceutically acceptable salt thereof as obtained by the said process was optionally isolated or treated in situ with the metal scavenger.
  • the compound of formula I or the pharmaceutically acceptable salt thereof can be treated twice with the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that when the compound of formula I or the pharmaceutically acceptable salt thereof; was treated with TPP as one of the metal scavenger, the other metal scavenger used was smopex ® 234.
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scave
  • the compound of formula I or the pharmaceutically acceptable salt thereof was isolated using isopropyl alcohol (IPA).
  • IPA isopropyl alcohol
  • the inventors of the present invention have observed that the compound of formula I or the pharmaceutically acceptable salt thereof; when treated twice with the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that when the compound of formula I or the pharmaceutically acceptable salt thereof was treated with TPP as one of the metal scavenger, the other metal scavenger was smopex ® 234 to obtain the compound of formula I or the pharmaceutically acceptable salt thereof; the Pd content is reduced to less than 1 ppm.
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger only once, it reduces the Pd content to some extent but does not provide the product, the compound of formula I or its pharmaceutically acceptable salt having Pd content less than 1 ppm.
  • the treatment of the compound of formula I only once with the metal scavenger is not sufficient to provide the compound of formula I or the pharmaceutically acceptable salt thereof having pharmaceutically acceptable purity.
  • the compound of formula I or the pharmaceutically acceptable salt thereof with Pd content less than 1 ppm is obtained by treating the compound of the formula I or the pharmaceutically acceptable salt thereof twice with the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.
  • the metal scavenger selected from the group consisting of smopex ® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex ® 234 or the mixture of triphenyl phosphin
  • dimeglumine salt of the compound of formula I (30g; Pd content 49ppm), methanol (150ml) and smopex ® 234 (1.5g) were added and the reaction mixture was stirred for 24 hours at 20-30°C.
  • the reaction mixture was filtered through hyflo.
  • triphenyl phosphine 1.5g was added and the reaction mixture was stirred for 24 hours at 20-30°C.
  • the reaction mixture was filtered through 0.4 micron. The filtrate was collected and added to the isopropyl alcohol (750ml) to precipitate a solid.
  • the precipitated solid was then filtered and washed with 30% methanol- isopropyl alcohol solution (30ml) followed by acetone (90ml). The solid was then dried under vacuum at a temperature of 20-30°C to yield dimeglumine salt of the compound of formula I. Yield 80%, purity 99%, Pd content: 0.57 ppm.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/IB2014/066279 2013-12-02 2014-11-24 An improved process for the preparation of fosaprepitant having improved purity WO2015083033A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432337A (zh) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 福沙匹坦衍生物、合成和在长效制剂中的用途
CN109608498A (zh) * 2018-12-25 2019-04-12 四川制药制剂有限公司 一种福沙匹坦超临界反应制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060110A2 (en) * 2004-11-05 2006-06-08 Merck & Co., Inc. Process for preparing {3-[2(r)-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(s)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid
WO2012164576A2 (en) * 2011-06-03 2012-12-06 Hetero Research Foundation Process for fosaprepitant
WO2013168176A2 (en) * 2012-03-30 2013-11-14 Glenmark Generics Limited Process for preparation of fosaprepitant and salt thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060110A2 (en) * 2004-11-05 2006-06-08 Merck & Co., Inc. Process for preparing {3-[2(r)-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(s)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid
WO2012164576A2 (en) * 2011-06-03 2012-12-06 Hetero Research Foundation Process for fosaprepitant
WO2013168176A2 (en) * 2012-03-30 2013-11-14 Glenmark Generics Limited Process for preparation of fosaprepitant and salt thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PHILLIPS S ET AL.: "The Use of Metal Scavengers for Recovery of Palladium Catalyst from Solution", PLATINUM METALS REV., vol. 54, no. 1, 2010, pages 69 - 70 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432337A (zh) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 福沙匹坦衍生物、合成和在长效制剂中的用途
CN109608498A (zh) * 2018-12-25 2019-04-12 四川制药制剂有限公司 一种福沙匹坦超临界反应制备方法

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