US20060076227A1 - Purification process - Google Patents

Purification process Download PDF

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Publication number
US20060076227A1
US20060076227A1 US10/522,828 US52282805A US2006076227A1 US 20060076227 A1 US20060076227 A1 US 20060076227A1 US 52282805 A US52282805 A US 52282805A US 2006076227 A1 US2006076227 A1 US 2006076227A1
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United States
Prior art keywords
terbinafine
ppm
distillation
free base
palladium
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Abandoned
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US10/522,828
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English (en)
Inventor
Ulrich Beutler
Gerhard Penn
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Individual
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Individual
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Application filed by Individual filed Critical Individual
Publication of US20060076227A1 publication Critical patent/US20060076227A1/en
Priority to US12/291,863 priority Critical patent/US7985323B2/en
Priority to US12/354,841 priority patent/US20100087545A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings

Definitions

  • the invention relates to a purification process for an allylamine pharmaceutical. It concerns a process for purifying crude terbinafine base.
  • Terbinafine particularly in the form of the hydrochloride acid addition salt form, is known from e.g. EP 24587. It belongs to the class of allylamine antimycotics. It is commercially available under the trademark LamisilR. It is effective upon both topical and oral administration, in a wide range of fungal infections. Terbinafine is particularly useful against dermatophytes, contagious fungi that invade dead tissues of the skin or its appendages such as stratum corneum, nail, and hair.
  • Terbinafine represents a significant advance in antifungal therapy based on its potent fungicidal action in vitro and rapid clinical efficacy in various dermatophyte infections when given orally as well as topically. It is a potent inhibitor of ergosterol biosynthesis ( Ann. NY Acad. Sci. 544 [1988] 46-62), it blocks the action of squalene epoxidase, thus inhibiting the transformation of squalene to squalene epoxide. Although ergosterol synthesis is only partially inhibited, cell growth is completely arrested.
  • terbinafine may be related to the accumulation of squalene, which at high concentrations may be toxic to the fungus.
  • the spectrum of activity of terbinafine in vitro embraces all dermatophytes of the genera Trichophyton, Epidermophyton and Microsporum. The mean minimum inhibitory concentrations for these dermatophytes range from 0.001 ⁇ g/ml to 0.01 ⁇ g/ml ( Science 224 [1984] 1239-1241).
  • Terbinafine is also active in vitro against molds and dimorphic fungi, and against many pathogenic yeasts of the genera Pityrosporum, Candida and Rhodotorula.
  • terbinafine is as shown in formula I and its chemical name is i.a.
  • An acid addition salt form can be prepared from the free base form in conventional manner and vice-versa.
  • suitable acid addition salt forms are the hydrochloride, the lactate, the ascorbate and the malate, e.g. the L-( ⁇ )-hydrogenmalate.
  • the free base and the hydrochloride and malate salts are preferred.
  • terbinafine is an allylamine compound with a triple bond conjugated with a double bond in the side chain.
  • Terbinafine was invented many years ago (see e.g. EP 24587, Example 16), and such conjugated enyne structure was, and still is, highly unusual in the pharmaceutical field, constituting a novel structural feature in medicinal chemistry.
  • conjugated enyne compounds e.g. the ether CH 3 CH ⁇ CH—C ⁇ C—CH 2 OC 2 H 5 to the corresponding 1,3,5-triene compound
  • isomerization of conjugated enyne compounds e.g. the ether CH 3 CH ⁇ CH—C ⁇ C—CH 2 OC 2 H 5 to the corresponding 1,3,5-triene compound
  • terbinafine base may be submitted to distillation with no particularly unfavourable effect. Further, it has been found that such distillation may be effected at elevated temperature, e.g. even at a temperature significantly higher than 100° C., e.g. from about 110° C. to about 170° C., preferably from about 125° C. to about 165° C., especially about 160° C., and under correspondingly reduced pressure, e.g. 0.2 mbar at 160° C. (jacket temperature).
  • the yield attained thereby is normally about 95% starting from crude product.
  • distillation may even be effected using large amounts of crude terbinafine base, i.e. in an industrial setting, e.g. in the large-scale production of purified terbinafine base and acid addition salts, e.g. in amounts of at least about 5 kg, preferably at least about 50 kg, especially at least about 200 kg, e.g. from about 500 kg to about 2 tons, more preferably from about 600 kg to about 900 kg, most preferably from about 800 kg to about 900 kg, especially about 850 kg purified product in free base form per distillation batch or run.
  • an industrial setting e.g. in the large-scale production of purified terbinafine base and acid addition salts, e.g. in amounts of at least about 5 kg, preferably at least about 50 kg, especially at least about 200 kg, e.g. from about 500 kg to about 2 tons, more preferably from about 600 kg to about 900 kg, most preferably from about 800 kg to about 900 kg, especially about 850 kg purified product in free
  • the invention therefore concerns a novel process for the purification of terbinafine comprising subjecting crude terbinafine in free base form to distillation and recovering the resultant product in free base or acid addition salt form, hereinafter briefly named “the process of the invention”.
  • the process of the invention is particularly useful for separating terbinafine from contaminants, e.g. metal contaminants resulting from its chemical synthesis, e.g. from catalysts, such as copper and/or, in particular, palladium contaminants, particularly for reducing or eliminating contaminants resulting from synthesis in accordance with or similarly to the processes described in e.g. Banyu EP 421302 and/or Dipharma EP 1,236,709, e.g.
  • the process of the invention may be effected by conventional means. It preferably is effected as a so-called “gentle” distillation process. It may e.g. be effected as a batch distillation, or preferably in continuous or semi-continuous manner, and especially as a “short path” distillation, whereby the path between heating mantle and condensor is short, e.g. of the order of 10 cm, thus minimizing the time during which terbinafine is at an elevated temperature, e.g. above 100° C.
  • short path distillation is to be understood herewith as a high vacuum distillation to separate mixtures of organic (or silicon) compounds that will not tolerate prolonged heating without excessive structural change or decomposition. It utilizes the heat of condensation as a prime body for radiant heat emission to the surface film of the evaporator. The path between evaporator and condenser is unobstructed. With short residence time and lower distillating temperatures, thermal hazard to the organic material is greatly reduced.
  • the process of the invention using short path distillation may be effected using commercially available apparatus, e.g. as commercialised by UIC GmbH, D-63755 Alzenau-Horstein, Germany.
  • a convenient setup is e.g. as illustrated in the Figure.
  • Short path distillation is preferred. It allows short heating time of the mixture which it is intended to purify, as well as cyclical processing, with corresponding improvement in yield of purified product. Further, thickness of the material on the evaporator wall is reduced, allowing lower evaporation temperature and shorter residence time. Very efficient separation from contaminants is achieved thereby, without need for further purification steps such as by chromatography or recrystallization, or using large amounts of charcoal.
  • one-step short path distillation results in a product containing less than 1 ppm copper, and/or less than 2 ppm palladium as determined using conventional analytical methods such as atom absorption spectroscopy.
  • the invention thus includes i.a.:
  • the crude terbinafine base used as a starting material is prepared by reaction of (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine and 3,3-dimethyl-1-butyne in n-butylamine and water in the presence of catalytic amounts of copper(I)iodide and bis-(triphenylphosphine)palladium(II)-dichloride along the lines as described in Example 13 of EP 421302 A2, but without submitting the resultant product to silicagel chromatography.
  • terbinafine base as a yellowish distillate is obtained, which is contaminated with 1 ppm palladium and less than 1 ppm copper.
  • the chemical purity of the distillate is 98.6% terbinafine base (i.e. E-isomer) as determined by gas chromatography (HP-1 column; crosslinked methyl siloxane; length 30 m; film thickness 2.65 ⁇ m; column internal diameter 0.53 mm; flame ionization detector (FID) temperature 300°; injector temperature 250°; temperature gradient 50° to 270°; heating rate 20°/min).
  • FID flame ionization detector
  • 10.5 g of distillation residue and 0.4 g of an oily sublimate were obtained.
  • the sublimate consists mainly of 2,2,7,7-tetramethylocta-3,5-diyne (by-product 2).
  • the overall purity of terbinafine base as determined by gas chromatography is as follows: Before distillation After distillation (crude product) (pure product) By-product 1 (area-%) 0.1 0.1 by-product 2 (area-%) 0.7 0.2 Z-isomer (area-%) 0.3 0.3 E-isomer (weight-%) 95.6 98.6 Pd (ppm) 177 1 Cu (ppm) 19 ⁇ 1
  • Distillation of crude terbinafine base is carried out in a fine vacuum distillation apparatus (UIC GmbH KD 150) using short-path distillation with two serial evaporators.
  • UIC GmbH KD 150 a fine vacuum distillation apparatus
  • the material is constantly fed and distributed to the inner surface of a vertically oriented evaporator.
  • an axially arranged roller wiper system distributes this liquid as a thin film which is constantly mixed (see Figure). This gentle distillation method therefore reduces both the maximum evaporation temperature and the residence time at high temperature.
  • the starting temperature values are typically set as follows:
  • a mixture of 872.5 kg crude terbinafine base (prepared analogously as described in Example 1 above) and 120 kg peanut oil is then transferred to the feeding tank.
  • the peanut oil will ensure that no crusts will build up inside the evaporators.
  • the cooling trap is filled with a mixture of 20 to 30 kg dry ice and about 30 l of ethanol (94 %), and temperature values are adjusted as follows:
  • the internal temperature of the main receiver is set to 50° as the melting point of the product is around 42°.
  • the crude product is fed to evaporator 1 with a flow of about 1.5 l/min.
  • the distillate (rest of solvents) of evaporator 1 can be collected in the gauge as its volume is small.
  • the residue of evaporator 1 is transferred to evaporator 2 to distill the crude base, which is collected in the heated main receiver (1.4 l/min) as a yellow liquid.
  • the new residue will be cycled through the evaporators until the flow of the product has reached around 0.2 1/h.
  • the jacket temperature of evaporator 1 is reduced to 100° and the condenser temperature of evaporator 2 is increased to 60°.
  • the received distillate becomes darker.
  • the apparatus is released with nitrogen.
  • the product from the main receiver is filled at around 50° into drums.
  • a sample is taken and the drums are weighed.
  • the chemical purity of the free base is 97% or higher (here it was 98.4%) as determined by gas chromatography.
  • the yield was 856.1 kg.
  • the amount of copper and/or palladium left was very small or undetectable (less than 1 ppm).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US10/522,828 2003-08-29 2004-08-27 Purification process Abandoned US20060076227A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/291,863 US7985323B2 (en) 2003-08-29 2008-11-14 Purification process
US12/354,841 US20100087545A1 (en) 2003-08-29 2009-01-16 Purification process

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0320312.2A GB0320312D0 (en) 2003-08-29 2003-08-29 Purification process
GB0320312.2 2003-08-29
PCT/EP2004/009587 WO2005021483A2 (en) 2003-08-29 2004-08-27 Process for the purification of terbinafine

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11/075,227 Continuation-In-Part US20050197512A1 (en) 2003-08-29 2005-03-08 Purification process
US12/291,863 Continuation US7985323B2 (en) 2003-08-29 2008-11-14 Purification process

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US20060076227A1 true US20060076227A1 (en) 2006-04-13

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US10/522,828 Abandoned US20060076227A1 (en) 2003-08-29 2004-08-27 Purification process
US12/291,863 Expired - Fee Related US7985323B2 (en) 2003-08-29 2008-11-14 Purification process

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US (2) US20060076227A1 (zh)
EP (1) EP1694631A2 (zh)
JP (1) JP5208416B2 (zh)
KR (2) KR101233024B1 (zh)
CN (1) CN100491334C (zh)
AR (1) AR045506A1 (zh)
AU (1) AU2004268051B2 (zh)
BR (1) BRPI0413896A (zh)
CA (1) CA2536498C (zh)
EC (1) ECSP066382A (zh)
GB (1) GB0320312D0 (zh)
IL (1) IL173709A (zh)
IS (1) IS8369A (zh)
MA (1) MA28030A1 (zh)
MX (1) MXPA06002348A (zh)
MY (1) MY149357A (zh)
NO (1) NO20061404L (zh)
NZ (1) NZ545445A (zh)
PE (1) PE20050873A1 (zh)
RU (1) RU2367649C2 (zh)
SG (1) SG145782A1 (zh)
TN (1) TNSN06066A1 (zh)
TW (1) TWI350829B (zh)
WO (1) WO2005021483A2 (zh)
ZA (1) ZA200601264B (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0503942D0 (en) * 2005-02-25 2005-04-06 Novartis Ag Purification process
EP1900378A1 (en) * 2006-08-31 2008-03-19 Novartis AG Pharmaceutical compositions for the treatment of fungal infections
BRPI0920522A2 (pt) 2008-09-05 2019-09-24 Travanti Pharma Inc embalagem para administração de fármaco iontoforético

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680291A (en) * 1977-08-19 1987-07-14 Sandoz Ltd. Propenylamines, processes for their production and pharmaceutical compositions containing them
US4755534A (en) * 1979-08-22 1988-07-05 Sandoz Ltd. Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals
US5132459A (en) * 1979-08-22 1992-07-21 Sandoz Ltd. Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals
US5436354A (en) * 1989-10-02 1995-07-25 Banyu Pharmaceutical Co., Ltd. Intermediates for producing enyne derivatives
US5817875A (en) * 1995-09-20 1998-10-06 Karimian; Khashayar Methods for the manufacture of terbinafine
US6515181B2 (en) * 2001-03-02 2003-02-04 Dipharma S.P.A. Process for the preparation of terbinafine
US7288678B2 (en) * 2002-11-29 2007-10-30 Dipharma S.P.A. Process for preparing terbinafine by using platinum as catalyst

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH678527A5 (en) 1989-06-22 1991-09-30 Sandoz Ag Trans(E)-N-(1-naphthyl:methyl)-heptenyl-amine prepn. - by simultaneously converting crude mixt. contg. cis and trans isomers to salt and precipitating trans isomer
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6770786B1 (en) 1999-10-22 2004-08-03 Richter Gedeon Vegyeszeti Gyar Rt. Process for preparing a substituted allylamine derivative and the salts thereof
GB2357762B (en) 2000-03-13 2002-01-30 Lundbeck & Co As H Crystalline base of citalopram
ITMI20010421A1 (it) * 2001-03-01 2002-09-02 Ausimont Spa Membrane porose semipermeabili di fluoropolimeri semicristallini
KR100459275B1 (ko) * 2001-12-28 2004-12-03 주식회사유한양행 터비나핀 또는 그의 염산염의 제조방법
US20060004230A1 (en) * 2004-06-30 2006-01-05 Joseph Kaspi Process for the preparation of terbinafine and salts thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680291A (en) * 1977-08-19 1987-07-14 Sandoz Ltd. Propenylamines, processes for their production and pharmaceutical compositions containing them
US4755534A (en) * 1979-08-22 1988-07-05 Sandoz Ltd. Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals
US5132459A (en) * 1979-08-22 1992-07-21 Sandoz Ltd. Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals
US5436354A (en) * 1989-10-02 1995-07-25 Banyu Pharmaceutical Co., Ltd. Intermediates for producing enyne derivatives
US5817875A (en) * 1995-09-20 1998-10-06 Karimian; Khashayar Methods for the manufacture of terbinafine
US6515181B2 (en) * 2001-03-02 2003-02-04 Dipharma S.P.A. Process for the preparation of terbinafine
US7288678B2 (en) * 2002-11-29 2007-10-30 Dipharma S.P.A. Process for preparing terbinafine by using platinum as catalyst

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CN100491334C (zh) 2009-05-27
IS8369A (is) 2006-03-23
NZ545445A (en) 2010-03-26
MA28030A1 (fr) 2006-07-03
IL173709A0 (en) 2006-07-05
RU2367649C2 (ru) 2009-09-20
AU2004268051A1 (en) 2005-03-10
GB0320312D0 (en) 2003-10-01
JP5208416B2 (ja) 2013-06-12
US7985323B2 (en) 2011-07-26
KR20060119892A (ko) 2006-11-24
ECSP066382A (es) 2006-09-18
AU2004268051B2 (en) 2009-03-05
TWI350829B (en) 2011-10-21
EP1694631A2 (en) 2006-08-30
CA2536498A1 (en) 2005-03-10
IL173709A (en) 2012-02-29
MXPA06002348A (es) 2006-05-22
KR101233024B1 (ko) 2013-02-13
RU2006109640A (ru) 2007-10-10
WO2005021483A2 (en) 2005-03-10
CA2536498C (en) 2012-10-09
WO2005021483A3 (en) 2005-05-12
PE20050873A1 (es) 2005-11-21
KR20120054109A (ko) 2012-05-29
NO20061404L (no) 2006-08-25
JP2007504110A (ja) 2007-03-01
BRPI0413896A (pt) 2006-10-24
ZA200601264B (en) 2007-06-27
US20090216047A1 (en) 2009-08-27
TNSN06066A1 (en) 2007-10-03
AR045506A1 (es) 2005-11-02
SG145782A1 (en) 2008-09-29
CN1845895A (zh) 2006-10-11
MY149357A (en) 2013-08-30
TW200523231A (en) 2005-07-16

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