WO2015084693A2 - Nouveau procédé de préparation de loratadine à partir d'un intermédiaire de cétone - Google Patents

Nouveau procédé de préparation de loratadine à partir d'un intermédiaire de cétone Download PDF

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Publication number
WO2015084693A2
WO2015084693A2 PCT/US2014/067846 US2014067846W WO2015084693A2 WO 2015084693 A2 WO2015084693 A2 WO 2015084693A2 US 2014067846 W US2014067846 W US 2014067846W WO 2015084693 A2 WO2015084693 A2 WO 2015084693A2
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WO
WIPO (PCT)
Prior art keywords
loratadine
solution
phosphonate
lithium
mixture
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Application number
PCT/US2014/067846
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English (en)
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WO2015084693A3 (fr
Inventor
Richard Desmond
Jungchul Kim
Robert A. Reamer
Jacob H. Waldman
Feng Xu
Original Assignee
Merck Sharp & Dohme Corp.
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Publication date
Application filed by Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Publication of WO2015084693A2 publication Critical patent/WO2015084693A2/fr
Publication of WO2015084693A3 publication Critical patent/WO2015084693A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present disclosure relates to a process for making loratadine from a ketone intermediate.
  • loratadine Processes for making loratadine are known (See U.S. Pat. No. 4,659, 716 and U.S. Pat. No. 6,271,378). An improved, robust process to prepare loratadine is disclosed herein. The new process employs an addition of HCl and an addition of an amide solvent for elimination and direct isolation of pure loratadine. DMAc is the preferred solvent of choice.
  • HCl replaces acetic acid which is typically used in the process to make loratadine.
  • HCl allows for better control of the impurity profile and makes the elimination step more reproducible.
  • DMAc replaces xylene which is typically used in the process to make loratadine.
  • the addition of DMAc avoids an aqueous extraction work-up and allows for direct crystallization of loratadine via the addition of water, optionally containing an aqueous pH modifier.
  • this new process offers significant manufacturing cost savings, process robustness with higher yield and without yield variation, and a reproducible high purity product (loratadine).
  • loratadine is produced in 82% isolated yield with no impurities >0.10A%.
  • This new process employs fewer steps, is greener as it reduces the volume of solvent used, and allows direct isolation of loratadine with improved yield.
  • a new optional recrystallization process has also been developed to ensure high quality loratadine.
  • This application is directed to a last step synthetic process for making loratadine from a ketone intermediate.
  • FIG. 1 Diffractogram of loratadine prepared by the instant process carried out on a
  • reaction mixture containing loratadine in solution to isolate crystalline loratadine (5) is obtained from a loratadine in solution to isolate crystalline loratadine (5).
  • a process for making loratadine comprising: a) adding an alkyl lithium dropwise to an amine in an ether solvent at a temperature of about 0 to about -70°C over about 0.5 to about 4 hours to form a solution of lithium amide;
  • reaction mixture containing loratadine in solution to isolate crystalline loratadine (5) is obtained from a loratadine in solution to isolate crystalline loratadine (5).
  • a process for making loratadine comprising: a) adding an alkyl lithium dropwise to an amine in an ether solvent at a temperature of about -20 to about -25°C over about 0.5 to about 4 hours to form a solution of lithium amide;
  • the charge range of amine is 1.0 - 1.7 equivalents. In another embodiment, the charge range of amine is 1.1 - 1.5 equivalents. In another embodiment, the charge range of amine is 1.2 - 1.4 equivalents. In another embodiment, the step a) amine is diisopropyl amine. In another embodiment, the charge range of diisopropyl amine is 1.0 - 1.7 equivalents. In another embodiment, the charge range of diisopropyl amine is 1.1 - 1.5 equivalents. In another embodiment, the charge range of diisopropyl amine is 1.2 - 1.4 equivalents.
  • the step a) ether solvent is THF.
  • the step a) addition of the alkyl lithium to the amine in an ether solvent which forms a solution of lithium amide is initiated at a temperature of about -0 to about -70°C. In another embodiment, the step a) addition of the alkyl lithium to the amine in an ether solvent is initiated at a temperature of about -5 to about -40°C. In another embodiment, the step a) addition of the alkyl lithium to the amine in an ether solvent is initiated at a temperature of about -20 to about -25°C.
  • the step a) addition of the alkyl lithium occurs dropwise over about 0.5-4 hours. In another embodiment, the step a) addition of the alkyl lithium occurs dropwise over about 1 hour.
  • the step a) addition of the alkyl lithium to the amine in an ether solvent which forms a solution of lithium amide is initiated at a temperature of about - 20 to about -25°C and then the solution is subsequently stirred and warmed to about -5 to about -10°C over about 30 minutes and then cooled to about -20 to about -25°C.
  • the charge range of alkyl lithium is 1.0 - 1.7. In another embodiment, the charge range of alkyl lithium is 1.1 - 1.4. In another embodiment, the charge range of alkyl lithium is 1.1 - 1.3. In another embodiment, the step a) alkyl lithium is butyl lithium. In another embodiment, the charge range of butyl lithium is 1.0 - 1.7. In another embodiment, the charge range of butyl lithium is 1.1 - 1.4. In another embodiment, the charge range of butyl lithium is 1.1 - 1.3.
  • the step b) phosphonate is in solution. In another embodiment the phosphonate is in THF. In another embodiment, the charge range of phosphonate is 1.0 - 1.5 equivalents. In another embodiment, the charge range of phosphonate is 1.1 - 1.4 equivalents. In another embodiment, the charge range of phosphonate is 1.1 - 1.3 equivalents.
  • the step b) lithium phosphonate anion reaction mixture is maintained at a temperature of about -35 to about -5°C. In another embodiment, the step b) lithium phosphonate anion reaction mixture is maintained at a temperature of about -30 to about -10°C. In another embodiment, the step b) lithium phosphonate anion reaction mixture is maintained at a temperature of about -25 to about -15°C.
  • the step b) lithium phosphonate anion reaction mixture is agitated for about 0.5-3 hours. In another embodiment, the step b) lithium phosphonate anion reaction mixture is agitated for about 1 hour.
  • the step c) ketone (2) is mixed with an organic solvent. In another embodiment the ketone (2) is in THF.
  • the step c) ketone solution is added to form a phosphonate adduct mixture which is maintained at a temperature of about -35 to about -5°C. In another embodiment, the step c) ketone solution is added to form a phosphonate adduct mixture which is maintained at a temperature of about -30 to about -10°C. In another embodiment, the step c) ketone solution is added to form a phosphonate adduct mixture which is maintained at a temperature of about -25 to about -15°C. In another embodiment, the step c) ketone solution is added to form a phosphonate adduct mixture which is maintained at a temperature of about -20°C.
  • the step c) ketone solution is added dropwise over about 0.5-3 hours to form a phosphonate adduct mixture which is maintained at a temperature of about -20°C. In another embodiment, the step c) ketone solution is added dropwise over about 1 hour to form a phosphonate adduct mixture which is maintained at a temperature of about - 20°C.
  • the step c) phosphonate adduct mixture is stirred for about 0.5-3 hours after the dropwise addition of the ketone solution. In another embodiment, the step c) phosphonate adduct mixture is stirred for about 1 hour after the dropwise addition of the ketone solution.
  • step d) HC1 is in solution. In another embodiment the
  • HC1 is in isopropanol.
  • the charge range of HQ is 2 - 5 equivalents.
  • the charge range of HC1 is 2.2 - 3.5 equivalents.
  • the charge range of HC1 is 2.5 - 3 equivalents.
  • reaction temperature after the step d) addition of HC1 is maintained from about -5 to about -35°C. In another embodiment, the reaction temperature after the step d) addition of HQ is maintained at about -10 to about -30°C. In another embodiment, the reaction temperature after the step d) addition of HC1 is maintained at about -15 to about -20°C.
  • the step d) addition of HQ occurs over about 0.5-2 hours. In another embodiment, the step d) addition of HQ occurs over about 30 minutes to about 1 hour.
  • step d) addition of HQ occurs over about 0.5 hour to about 1 hour, wherein the cyclic phosphonate intermediate mixture is warmed to ambient temperature.
  • the step e) amide solvent is added to the HC1 quenched reaction mixture.
  • the step e) amide solvent is selected from DMAc, DMF and NMP.
  • the step e) amide solvent is DMAc.
  • the reaction temperature after the step e) addition of the amide solvent is increased to about 100 to about 150°C.
  • the reaction temperature after the step e) addition of the amide solvent is increased to about 125 to about 140°C.
  • the reaction temperature after the step e) addition of the amide solvent is increased to about 100 to about 150°C and agitated for about an additional 4 hours.
  • reaction temperature after the step e) addition of the amide solvent is increased to about 125 to about 140°C and agitated for about an additional 2 hours. In an embodiment, the reaction temperature after the step e) addition of the amide solvent is increased to about 100 to about 150°C and agitated for about an additional 4 hours, wherein the reaction mixture is cooled to about 50°C. In another embodiment, the reaction temperature after the step e) addition of the amide solvent is increased to about 125 to about 140°C and agitated for about an additional 2 hours, wherein the reaction mixture is cooled to about 50°C.
  • the step f) water contains an aqueous pH modifier. In another embodiment, the step f) water contains an aqueous pH modifier which is aHC0 3 . In another embodiment, the step f) water contains an aqueous pH modifier which is 5% NaHC03. In another embodiment, the step f) aqueous pH modifier is selected from NaHCCh and a 2 C0 3 . In another embodiment, the step f) aqueous pH modifier is aHC0 3 .
  • step f) addition of water containing NaHCC ⁇ is followed by the dropwise addition of water over about 5 hours. In another embodiment, the step f) addition of water containing NaHCC ⁇ is followed by the dropwise addition of water over about 2 hours.
  • step f) addition of water containing 5% aHC0 3 is followed by the dropwise addition of water over about 5 hours.
  • step f) addition of water containing 5% NaHCC ⁇ is followed by the dropwise addition of water over about 2 hours.
  • THF tetrahydrofuran
  • Amine means diisopropyl amine or other di-alkyl amine.
  • Ether solvent means a class of organic compounds that contain an ether group— an oxygen atom connected to two alkyl or aryl groups, cyclic or acyclic— of general formula R-O-R'.
  • Alkyl lithium means a substituted or unsubstituted Ci-Cs alkyl lithium.
  • DMAc means dimethylacetimide
  • DMF means d meihy ⁇ form am ide .
  • NMP means N-metliyl-2-pyiTo3idone
  • Preferred aqueous pH modifiers are aHC0 3 and a 2 C0 3 .
  • the lithium phosphonate anion is meant to refer to the deprotonated form- the anion formed by deprotonating the hydrogen on the carbon adjacent to the phosphonate.
  • the lithium anion phosphonate reaction mixture is, under these conditions, a slurry.
  • Aqueous NaHCC is utilized as the "aqueous pH modifier", while other aqueous pH modifiers may be used.
  • the function of the aqueous pH modifier is to improve crystalline loratadine recovery.
  • certain equivalents of pH modifier may be used such as 5% NaHCC at 1.5X volume, or 1-3X volume, or 0-6X volume.
  • H 2 O a certain additional volume of H 2 O may be utilized such as 4.5X volume, or 3-6X volume, or 0-8X volume.
  • the standard amounts of crystalline loratadine to be used for seeding include about 0.3% to about 1%, or 0.2% to about 5%, or 0.1 to about 10%.
  • Powder X-ray Diffraction data were acquired on a Panalytical X-pert Pro PW3040 System configured in the Bragg-Brentano configuration and equipped with a Cu radiation source with monochromatization to Ka achieved using a Nickel filter. A fixed slit optical configuration was employed for data acquisition. Data (as shown in FIG. 1.) were acquired between 2 and 40° 2 ⁇ . Samples were prepared by gently pressing powdered sample onto a shallow cavity zero background silicon holder.
  • the above toluene solution was hydrogenated in the presence of 20 wt% Pd(OH) 2 /C (3.88 g) under hydrogen (300 psi) at 25 °C for 18 h.
  • the batch was filtered through solka floe.
  • the catalyst was washed with toluene (100 mL).
  • the filtrate was azeotropically concentrated in vacuum to give 79.5 g of the phosphonate with 89.6 wt% purity containing -7.2 wt% residual toluene. 88% isolated yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un procédé de synthèse de dernière étape destiné à fabriquer de la loratadine à partir d'un intermédiaires de cétone.
PCT/US2014/067846 2013-12-05 2014-12-01 Nouveau procédé de préparation de loratadine à partir d'un intermédiaire de cétone WO2015084693A2 (fr)

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US61/912,133 2013-12-05

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WO2015084693A3 WO2015084693A3 (fr) 2015-10-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016206028A1 (fr) * 2015-06-24 2016-12-29 苏州大学张家港工业技术研究院 Procédé de préparation de phosphate de cyclopropyle
CN106478595A (zh) * 2016-09-18 2017-03-08 西安交通大学 氯雷他定晶型及其制备方法和用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271378B1 (en) * 1998-12-18 2001-08-07 Schering Corporation Process for preparing tricyclic compounds having antihistaminic activity
ITMI20012308A1 (it) * 2001-11-05 2003-05-05 Zambon Spa Processo per la preparazione dell'estere etilico dell'acido 4-(8-cloro-5,6-diidro-11h-benzo-5,67-cicloepta-1,2-b-piridin-11-ilidene)-1-piper
US20080194823A1 (en) * 2006-04-04 2008-08-14 Mayur Devjibhai Khunt Preparation of loratadine form i
CN102336739B (zh) * 2011-07-15 2012-09-26 海南灵康制药有限公司 一种氯雷他定化合物及其制法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016206028A1 (fr) * 2015-06-24 2016-12-29 苏州大学张家港工业技术研究院 Procédé de préparation de phosphate de cyclopropyle
CN106478595A (zh) * 2016-09-18 2017-03-08 西安交通大学 氯雷他定晶型及其制备方法和用途

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