WO2007052089A1 - A process for the purification of 1-halo-6,6-dimethyl-hept-2-ene-4-yne - Google Patents

A process for the purification of 1-halo-6,6-dimethyl-hept-2-ene-4-yne Download PDF

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Publication number
WO2007052089A1
WO2007052089A1 PCT/IB2005/003421 IB2005003421W WO2007052089A1 WO 2007052089 A1 WO2007052089 A1 WO 2007052089A1 IB 2005003421 W IB2005003421 W IB 2005003421W WO 2007052089 A1 WO2007052089 A1 WO 2007052089A1
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Prior art keywords
dimethyl
ene
hept
yne
formula
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PCT/IB2005/003421
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French (fr)
Inventor
Vijay Kumar Handa
Shankar Rama
Asif Pervez Sayyed
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C07C17/383—Separation; Purification; Stabilisation; Use of additives by distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings

Definitions

  • the present invention relates to a process for the purification of l-halo-6,6- dimethyl-hept-2-ene-4-yne (Formula I).
  • This compound is an important intermediate for the production of the widely used antifungal drug Terbinafme.
  • l-Halo-6,6-dimethyl-hept-2-ene-4-yne is an intermediate, which is useful in the preparation of (E)-N-methyl-N-(l -naphthylmethyl)-6,6-dimethylhept-2-ene-4- ynyl-1 -amine, generically known as Terbinafme of Formula II.
  • Terbinafme in the form of hydrochloride salt, is presently marketed with the Trade name LAMISIL.
  • Terbinafme is an orally active antifungal agent, preferably used against mycosis caused by dermathophytons on the skin and on the nails.
  • US 4,755,534 discloses a process to prepare l-bromo-6,6-dimethyl-hept-2-ene-4- yne, which comprises treating an alcoholic solution of 6,6-dimethyl-hept-l-ene- 4-yn-3-ol with a mixture of HBr and PBr 3 at 1O 0 C followed by stirring at room temperature.
  • the reaction has been worked-up by pouring the mixture into ice and extracting the product with hexane several times.
  • the organic layer is washed number of times with aqueous sodium chloride,
  • US 5,021,446 describes a process to prepare l-chloro-6,6-dimethyl-hept-2-ene-4- yne, which comprises treating a hexane solution of 6,6-dimethyl-hept-l-ene-4-yn- 3-ol with thionyl chloride in presence of a catalytic amount of N,N- dimethylformamide. Thereafter, the reaction mass is concentrated under reduced pressure to get the crude product, which is used in subsequent process without any further purification.
  • Tetrahedron Letters, 41, 3895-3898 (2000) describes a process to prepare 1- chloro-6,6-dimethyl-hept-2-ene-4-yne, which comprises reacting 6,6-dimethyl- hept-l-ene-4-yn-3-ol with boron trichloride in n-hexane medium at 15-20 0 C. Thereafter, the mixture is quenched with water and organic layer is separated. Subsequently, the organic layer is washed with 20% sodium chloride solution, dried over anhydrous magnesium sulfate and solvent is evaporated to obtain the product.
  • WO 01/28976 describes another process for preparing l-chloro-6,6-dimethyl- hept-2-ene-4-yne where the alcohol derivative 6,6-dimethyl-hept-l-ene-4-yn-3-ol is treated with aqueous hydrochloric acid. Thereafter, the product is extracted in methyl isobutyl ketone (MIBK) and the solution is washed with water and taken as such for condensation with N-methyl-N-(l-naphthylmethyl)aniine of Formula III to obtain Terbinafme.
  • MIBK methyl isobutyl ketone
  • US 2005/0197512 discloses a process for purification of Terbinafine base, which comprises short path distillation of crude Terbinafine base at a temperature above 100 0 C (about 150°C) and under reduced pressure (0.2 mbar). By this distillation, Terbinafine has been purified to lower the content of a contaminant namely, 2(£),4(£)-iV-(4-[(N'-methyl-N / -l-na ⁇ hthylmethyl)ammomethyl]-8,8-dimethyl-2,4-
  • nonadien-6-inyl)-iV-methyl-l-na ⁇ hthylmethanamine of Formula IV from 60-80 ppm to less than 5 ppm.
  • the content of Formula IV contaminant should not exceed 5 ppm. Manufacturers have to control this contaminant of Formula IV in Terbinafine drug substance for safety and Regulatory marketing approvals.
  • Terbinafine is a conjugated enyne structure wherein a triple bond is inconjugation with a double bond. This conjugated system has limited thermal stability and is susceptible to decomposition or degradation or polymerization at elevated temperatures.
  • the reported boiling point for Terbinafine base is 140°C at 0.3 mbar pressure.
  • Terbinafine base becomes solid at 43 0 C.
  • the inherent thermally unstable chemical structure of Terbinafine base, its high boiling temperature and high melting temperature make this distillation process unattractive and disadvantageous for industrial production.
  • the aim of the present invention is to provide a highly efficient method to produce Terbinafine base that contains less than 5 ppm of impurity of Formula IV. This involves purification of l-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula I prior to subjecting it to Terbinafine preparation.
  • the present invention relates to a process for the purification of l-halo-6,6- dimethyl-hept-2-ene-4-yne of Formula I,
  • halogen atom such as ITuoro, Chloro or Bromo atom, which comprises subjecting crude l-halo-6,6-dimethyl-hept-2-ene-4-yne to distillation under reduced pressure to obtain pure l-halo-6,6-dimethyl-hept-2-ene-4-yne.
  • the pure l-halo-6,6-dimethyl- hept-2-ene-4-yne is reacted with iV-methyl-1-naphthalenemethylamine to yield Terbinafine and its pharmaceutically acceptable salts, which contain less than 5 ppm of contaminant of Formula IV -
  • the contaminant of Formula IV arises due to presence of the corresponding dihalide compound, (2£,4£)-l-halo-4-(halomethyl)-8,8-dimethyl-2,4-nonadien-6- yne, of Formula V,
  • halo intermediate of Formula I wherein X represents a halogen atom.
  • the synthesis of halo intermediate of Formula I utilizes acrolein as one of the raw materials.
  • Acrolein is known for its tendency towards polymerization under almost any condition and therefore compound of Formula I invariably contain polymeric material. It is advantageous to purify this compound by distillation before subjecting it to manufacture of Terbinafine. The distillation of compound of Formula I results in removal of the polymeric material as well as the dihalide compound of Formula V.
  • halo compound of Formula I may be submitted to distillation with no particular unfavourable effect. Further, it has been found that such distillation may be effected at a temperature below 100 0 C under corresponding reduced pressure of about 5 mm.
  • the preferred distillation technique is the fractional distillation.
  • the major advantage of the present invention is that contaminant of Formula IV can be reduced to less than 5 ppm in Terbinafine base by carrying out the distillation of l-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula I prior to subjecting it to preparation of Terbinafine.
  • distillation of Terbinafine base has been carried out to reduce contaminant of Formula IV to less than 5 ppm.
  • Terbinafine base has been carried out at high temperature of about 160°C and reduced pressure of 0.2 mbar whereas l-halo-6,6- dimethyl-hept-2-ene-4-yne of Formula I can be distilled at a comparatively lower temperature of below 100°C at about 5 mm of reduced pressure, making Terbinafine manufacture efficient and economical.
  • N-Methyl-l-naplithylmethylamine 100 g was dissolved in water (250 ml).
  • Sodium hydroxide 41.50 g was dissolved in water (120 ml) and this aqueous sodium hydroxide solution was added to N-Met ⁇ yl-I-napththyliriethylatnine solution at 20-40 0 C.
  • the reaction mass was heated to 90-95 0 C and l-chloro-6,6- dimethyl-hept-2-ene-4-yne (96 g, crude viscous oily mass having chromatographic purity by GC 92.40%, as obtained in Step A) was added at 90- 100°C.
  • the reaction mass was stirred at 90-100 0 C for 2 hrs and then cooled to room temperature.
  • Methylene chloride (400 ml) was added and organic layer separated.
  • the methylene chloride extract was washed with water (150 ml).
  • the washed methylene chloride solution was stirred with 300 ml dilute hydrochloric acid at room temperature for 1 h.
  • the methylene chloride layer was washed with water (100 ml) and treated with carbon (4 g) at room temperature.
  • the methylene chloride was stripped to get a residue.
  • the residue was refluxed for 30 min with ethyl acetate (600 ml).
  • the product slurry was cooled to room temperature and stirred for 30 min.
  • step B The same procedure as described in Example 1, step B was repeated, except that purified l-chloro-6,6-dimethyl-hept-2-ene-4-yne (as obtained after fractional distillation in Example 1 , Step A) was used instead of crude to obtain Terbinaf ⁇ ne hydrochloride which contained Impurity of Formula IV less than 2 ppm.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a process for purification of 1-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula (I), wherein X represents a halogen atom subjecting crude 1-halo-6,6-dimethyl-hept-2-ene-4-yne to distillation under reduced pressure to obtain pure 1-halo-6,6-dimethyl-hept-2-ene-4-yne. This compound is an important intermediate for the production of the widely used antifungal drug Terbinafine.

Description

A PROCESS FOR THE PURIFICATION OF 1-HALO-6.6-DIMETHYL-
HEPT-2-ENE-4-YNE
FIELD OF THE INVENTION
The present invention relates to a process for the purification of l-halo-6,6- dimethyl-hept-2-ene-4-yne (Formula I). This compound is an important intermediate for the production of the widely used antifungal drug Terbinafme.
Formula I
Figure imgf000002_0001
wherein X represents a halogen atom.
BACKGROUND OF THE INVENTION l-Halo-6,6-dimethyl-hept-2-ene-4-yne is an intermediate, which is useful in the preparation of (E)-N-methyl-N-(l -naphthylmethyl)-6,6-dimethylhept-2-ene-4- ynyl-1 -amine, generically known as Terbinafme of Formula II. Terbinafme, in the form of hydrochloride salt, is presently marketed with the Trade name LAMISIL. Terbinafme is an orally active antifungal agent, preferably used against mycosis caused by dermathophytons on the skin and on the nails.
Formula II
Figure imgf000002_0002
US 4,755,534 discloses a process to prepare l-bromo-6,6-dimethyl-hept-2-ene-4- yne, which comprises treating an alcoholic solution of 6,6-dimethyl-hept-l-ene- 4-yn-3-ol with a mixture of HBr and PBr3 at 1O0C followed by stirring at room temperature. The reaction has been worked-up by pouring the mixture into ice and extracting the product with hexane several times. The organic layer is washed number of times with aqueous sodium chloride,
dried and concentrated. The concentrated oily mass, which contains ~3:1 mixture of trans- and cis- l-bromo-6,6-dimethyl-hept-2-ene-4-yne is taken directly for alkylation reaction with iV-methyl-iV-(l-iiaphthylmethyl)amine to prepare Terbinafme.
US 5,021,446 describes a process to prepare l-chloro-6,6-dimethyl-hept-2-ene-4- yne, which comprises treating a hexane solution of 6,6-dimethyl-hept-l-ene-4-yn- 3-ol with thionyl chloride in presence of a catalytic amount of N,N- dimethylformamide. Thereafter, the reaction mass is concentrated under reduced pressure to get the crude product, which is used in subsequent process without any further purification.
Tetrahedron Letters, 41, 3895-3898 (2000) describes a process to prepare 1- chloro-6,6-dimethyl-hept-2-ene-4-yne, which comprises reacting 6,6-dimethyl- hept-l-ene-4-yn-3-ol with boron trichloride in n-hexane medium at 15-200C. Thereafter, the mixture is quenched with water and organic layer is separated. Subsequently, the organic layer is washed with 20% sodium chloride solution, dried over anhydrous magnesium sulfate and solvent is evaporated to obtain the product.
WO 01/28976 describes another process for preparing l-chloro-6,6-dimethyl- hept-2-ene-4-yne where the alcohol derivative 6,6-dimethyl-hept-l-ene-4-yn-3-ol is treated with aqueous hydrochloric acid. Thereafter, the product is extracted in methyl isobutyl ketone (MIBK) and the solution is washed with water and taken as such for condensation with N-methyl-N-(l-naphthylmethyl)aniine of Formula III to obtain Terbinafme. As evident, none of the above cited prior-art procedures disclose purification of 1- halo-6,6-dimethyl-hept-2-ene-4-yne of Formula I. This compound of Formula I has been used as such, without any purification, in the preparation of Terbinafine and its pharmaceutically acceptable salts as shown below:
X-H2C-CH=CH-C≡
Figure imgf000004_0001
(E)- and (Z)- Isomers
HI
Figure imgf000004_0002
(E)- Isomers II
US 2005/0197512 discloses a process for purification of Terbinafine base, which comprises short path distillation of crude Terbinafine base at a temperature above 1000C (about 150°C) and under reduced pressure (0.2 mbar). By this distillation, Terbinafine has been purified to lower the content of a contaminant namely, 2(£),4(£)-iV-(4-[(N'-methyl-N/-l-naρhthylmethyl)ammomethyl]-8,8-dimethyl-2,4-
nonadien-6-inyl)-iV-methyl-l-naρhthylmethanamine of Formula IV from 60-80 ppm to less than 5 ppm.
Formula IV
Figure imgf000004_0003
For Terbinafme drug substance to be acceptable for human administration, the content of Formula IV contaminant should not exceed 5 ppm. Manufacturers have to control this contaminant of Formula IV in Terbinafine drug substance for safety and Regulatory marketing approvals.
Terbinafine is a conjugated enyne structure wherein a triple bond is inconjugation with a double bond. This conjugated system has limited thermal stability and is susceptible to decomposition or degradation or polymerization at elevated temperatures. The reported boiling point for Terbinafine base is 140°C at 0.3 mbar pressure. Also, Terbinafine base becomes solid at 430C. The inherent thermally unstable chemical structure of Terbinafine base, its high boiling temperature and high melting temperature make this distillation process unattractive and disadvantageous for industrial production.
The aim of the present invention is to provide a highly efficient method to produce Terbinafine base that contains less than 5 ppm of impurity of Formula IV. This involves purification of l-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula I prior to subjecting it to Terbinafine preparation.
SUMMARY OF THE INVENTION
The present invention relates to a process for the purification of l-halo-6,6- dimethyl-hept-2-ene-4-yne of Formula I,
CH 3 Formula I
H3C-C-C≡C-CH=CH-CH2X CH3
where X represent? ?. halogen atom such as ITuoro, Chloro or Bromo atom, which comprises subjecting crude l-halo-6,6-dimethyl-hept-2-ene-4-yne to distillation under reduced pressure to obtain pure l-halo-6,6-dimethyl-hept-2-ene-4-yne. In another embodiment of the present invention, the pure l-halo-6,6-dimethyl- hept-2-ene-4-yne is reacted with iV-methyl-1-naphthalenemethylamine to yield Terbinafine and its pharmaceutically acceptable salts, which contain less than 5 ppm of contaminant of Formula IV -
Formula IV
Figure imgf000006_0001
DETAILED DESCRIPTION OF THE INVENTION
The contaminant of Formula IV arises due to presence of the corresponding dihalide compound, (2£,4£)-l-halo-4-(halomethyl)-8,8-dimethyl-2,4-nonadien-6- yne, of Formula V,
Formula V
Figure imgf000006_0002
where X represents a halogen atom
in the halo intermediate of Formula I, which is used in the preparation of Terbinafine.
Formula I
Figure imgf000006_0003
wherein X represents a halogen atom. The synthesis of halo intermediate of Formula I utilizes acrolein as one of the raw materials. Acrolein is known for its tendency towards polymerization under almost any condition and therefore compound of Formula I invariably contain polymeric material. It is advantageous to purify this compound by distillation before subjecting it to manufacture of Terbinafine. The distillation of compound of Formula I results in removal of the polymeric material as well as the dihalide compound of Formula V.
It has been found that halo compound of Formula I may be submitted to distillation with no particular unfavourable effect. Further, it has been found that such distillation may be effected at a temperature below 1000C under corresponding reduced pressure of about 5 mm. The preferred distillation technique is the fractional distillation.
It has been found that the purified halo compound thus obtained gives Terbinafine base that contains contaminant of Formula IV below 5 ppm.
The major advantage of the present invention is that contaminant of Formula IV can be reduced to less than 5 ppm in Terbinafine base by carrying out the distillation of l-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula I prior to subjecting it to preparation of Terbinafine. In the prior art procedure, distillation of Terbinafine base has been carried out to reduce contaminant of Formula IV to less than 5 ppm. This distillation of Terbinafine base has been carried out at high temperature of about 160°C and reduced pressure of 0.2 mbar whereas l-halo-6,6- dimethyl-hept-2-ene-4-yne of Formula I can be distilled at a comparatively lower temperature of below 100°C at about 5 mm of reduced pressure, making Terbinafine manufacture efficient and economical.
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. EXAMPLE 1
STEP A
PREPARATION OF (2E AND 2Z)-I-CHLORO-O5O-DIMETHYL-I-HEPT-I-
ENE-4-YNE
Hydrochloric acid (380 ml) was added slowly to a cooled (2-50C) mixture of 6,6- dimethyl-hept-l-ene-4-yn-3-ol (100 g) and toluene (140 ml) at 2-1O0C. The reaction mixture was stirred at 8-1O0C for 8 h. Thereafter, it was diluted with toluene (300 ml) followed by water (350 ml). The reaction mass was stirred for 10 minutes at 20-300C. The mass was filtered through hyflo and layers were separated. The organic layer was washed with aqueous sodium chloride (15% w/w, 100 ml) followed by aqueous sodium bicarbonate solution (8% w/w,
50 ml). The washed organic layer was concentrated by distilling toluene at 45-65°C under reduced pressure (100-30 mm Hg) till no more toluene distils. The crude product, (2E and 2Z)-l-chloro-6,6-dimethyl-2-hept-2-ene-4-yne [viscous oily mass, HO g, 97% yield, chromatographic purity (by GC), E- and Z- isomers together 92.40%] was obtained.
The crude product was subjected to fractional distillation under reduced pressure and purified (2E and 2Z)-l-chloro-6,6-dimethyl-2-hept-2-ene-4-yne was collected at 64-750C / 2-6 mm Hg [Yield 81 g, Chromatographic purity (by GC) E- and Z- isomers together 97.36%).
STEP B
PREPARATION OF TERBINAFINE HYDROCHLORIDE
N-Methyl-l-naplithylmethylamine (100 g) was dissolved in water (250 ml). Sodium hydroxide (41.50 g) was dissolved in water (120 ml) and this aqueous sodium hydroxide solution was added to N-Met^yl-I-napththyliriethylatnine solution at 20-400C. The reaction mass was heated to 90-950C and l-chloro-6,6- dimethyl-hept-2-ene-4-yne (96 g, crude viscous oily mass having chromatographic purity by GC 92.40%, as obtained in Step A) was added at 90- 100°C. The reaction mass was stirred at 90-1000C for 2 hrs and then cooled to room temperature. Methylene chloride (400 ml) was added and organic layer separated. The methylene chloride extract was washed with water (150 ml). The washed methylene chloride solution was stirred with 300 ml dilute hydrochloric acid at room temperature for 1 h. The methylene chloride layer was washed with water (100 ml) and treated with carbon (4 g) at room temperature. The methylene chloride was stripped to get a residue. The residue was refluxed for 30 min with ethyl acetate (600 ml). The product slurry was cooled to room temperature and stirred for 30 min. Product was filtered and washed with preheated ethyl acetate (160 ml, 40-450C). Product was dried at 55-600C under reduced pressure for 4 h to yield 104 g of Terbinafϊne hydrochloride, containing 1087 ppm of impurity of Formula IV.
EXAMPLE 2
PREPARATION OF TERBINAFINE HYDROCHLORIDE
The same procedure as described in Example 1, step B was repeated, except that purified l-chloro-6,6-dimethyl-hept-2-ene-4-yne (as obtained after fractional distillation in Example 1 , Step A) was used instead of crude to obtain Terbinafϊne hydrochloride which contained Impurity of Formula IV less than 2 ppm.

Claims

WE CLAIM
1. A process for the purification of l-lialo-6,6-dimethyl-hept-2-ene-4-yne of Formula I,
CH3 H3C-C-C=C-CH=CH-CH2X Formula I
CH 3
wherein X represents a halogen atom, which comprises subjecting crude 1- halo-6,6-dimethyl-hept-2-ene-4-yne to distillation under reduced pressure to obtain pure l-halo-6,6-dimethyl-hept-2-ene-4-yne
2. The process according to claim 1, wherein the purification is carried out using fractional distillation.
3. The process according to claim 2, wherein purified l-chloro-6,6-dimethyl- hept-2-ene-4-yne is obtained by fractional distillation at 64-750C / 2-6 mm Hg.
4. A process for preparing Terbinafine or a pharmaceutically acceptable salt thereof containing less than 5 ppm contaminant of Formula IV by reacting l-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula I, prepared according to claim 1, with JV-methyl-1-naphthylmethanamine of Formula III.
Formula III
Figure imgf000010_0001
PCT/IB2005/003421 2005-11-02 2005-11-02 A process for the purification of 1-halo-6,6-dimethyl-hept-2-ene-4-yne WO2007052089A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770786B1 (en) * 1999-10-22 2004-08-03 Richter Gedeon Vegyeszeti Gyar Rt. Process for preparing a substituted allylamine derivative and the salts thereof
US20050197512A1 (en) * 2003-08-29 2005-09-08 Ulrich Beutler Purification process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770786B1 (en) * 1999-10-22 2004-08-03 Richter Gedeon Vegyeszeti Gyar Rt. Process for preparing a substituted allylamine derivative and the salts thereof
US20050197512A1 (en) * 2003-08-29 2005-09-08 Ulrich Beutler Purification process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHOU S-Y ET AL: "A stereoselective synthesis of (E)-1-halo-6,6-dimethyl-2-hepten-4-yne: a key intermediate for terbinafine", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 41, no. 20, May 2000 (2000-05-01), pages 3895 - 3898, XP004203282, ISSN: 0040-4039 *

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