WO2007000628A1 - Intermediate of amorolfine or its salt - Google Patents
Intermediate of amorolfine or its salt Download PDFInfo
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- WO2007000628A1 WO2007000628A1 PCT/IB2006/000022 IB2006000022W WO2007000628A1 WO 2007000628 A1 WO2007000628 A1 WO 2007000628A1 IB 2006000022 W IB2006000022 W IB 2006000022W WO 2007000628 A1 WO2007000628 A1 WO 2007000628A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/62—Quaternary ammonium compounds
- C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
Definitions
- the present invention relates to a quaternary ammonium salt useful as an intermediate in the preparation of amorolfine and its salt. Further, the invention also relates to the preparation of the intermediate.
- Amorolfine is a morpholine derivative of Formula A,
- GB 1,589,253 discloses the reaction of 3-(p-tert.amyl-phenyl-2, 3-dimethyl allyl alcohol with phosphorous tribromide in pentane and pyridine to form 3-(p-tert.amyl- phenyl-2, 3-dimethyl allyl bromide.
- These allyl bromide derivatives have been isolated as a liquid, although with low purity. Also, these allyl bromide derivatives are thermally unstable to distillation. These allyl bromide derivatives get partially decomposed therefore they are carried as such without purification which affects ultimately the purity of amorolfine or its salts.
- a novel quaternary ammonium salt, (2E)-3-[4-(l,l-dimethylpropyl) phenyl] -N, N, N-triethyl-2-methylprop-2-ene-l -ammonium bromide of Formula I is provided.
- Formula II with phosphorous tri or penta bromide in the presence of triethyl amine. Further the compound of Formula I may be converted to amorolfine or its salts by conventional methods.
- Figure 2 is a table of peak positions and intensities derived from Figure 1. Detailed Description of the Invention
- the compound of Formula I which is (2E)-3-[4-(l,l-dimethylpropyl) phenyl]-N, N, N-triethyl-2-methylprop-2-ene-l -ammonium bromide is stable and solid, and may be used as a potential intermediate in the preparation of amorolfine or its salts. It may be characterized by its X-ray diffraction pattern, its NMR spectrum or its mass spectrum. It is solid and crystalline in nature. The crystalline compound of Formula I may be characterized by strong X-ray peaks at about 3.64 ⁇ 0.2 and 14.62 ⁇ 0.2 degrees two-theta.
- the reaction of a compound of Formula II with phosphorous tri or penta bromide may be carried out in the presence of halogenated hydrocarbons.
- halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof.
- Phosphorous tri or penta bromide may be added to the compound of Formula II in the form of a mixture in halogenated hydrocarbon. The addition may be carried out over about 1 to about 3 hours. The addition of phosphorous tri or penta bromide may be carried out at about -15 0 C to about 15°C. Excess of triethyl amine may be added to the reaction mixture for conversion of a compound of Formula II to a compound of Formula I.
- the compound of Formula I may be converted to amorolfine or its salt by the methods known to those skilled in the art, including GB 1,589,253, which is herein, incorporated by reference. In general, it may be prepared by reacting a compound of Formula I with 2,6 dimethyl morpholine followed by hydrogenation and purification to obtain pure amorolfine hydrochloride.
- distilled water 250 ml was added, and the mixture was stirred for 15 minutes at 0 to -5 0 C.
- the organic layer was separated and the aqueous layer was extracted by distilled water (150 ml).
- the organic layer was again separated at room temperature.
- the organic layers were combined and washed with distilled water (500 ml).
- the organic layer was concentrated completely at 30 to 35 0 C to get viscous liquid.
- the above viscous liquid was suspended with ethyl acetate at 20 to 25 0 C and triethyl amine (24.33g) was added slowly at 20 to 35°C. The reaction mixture was stirred at this temperature for 2 hours.
- (2E)-3-[4-(l,l-dimethylpropyl) phenyl]-N, N, N-triethyl-2-methylprop-2-ene-l- ammonium bromide (0.35 Kg) obtained above was stirred with toluene (3.5 liters) at room temperature.
- Cis-2, 6-dimethylmorpholine (0.116 Kg) was added to the above mixture within 20 minutes at same temperature.
- the reaction mixture was then refluxed at 110 to 112°C for 8 hours.
- the reaction was monitored by HPLC until the starting material was not more than 1% (w/w).
- the reaction mixture was then cooled to room temperature and 5% aqueous sodium hydroxide (1.0 liter) was charged.
- Dehydroamorolfine hydrochloride (0.2 Kg), hydrochloric acid (20 ml) and 10% palladium carbon (20 g, 50% wet) were added in methanol (1.2 liters) at room temperature. Hydrogen gas was purged into the mixture for 3 hours at room temperature. The reaction was monitored by HPLC till dehydroamorolfine was not more than 0.1% (w/w). The reaction mixture was filtered through hyflo bed under nitrogen atmosphere. The hyflo bed was washed with methanol twice (400 ml each). All the filtrates were combined and methanol was recovered under reduced pressure at 45 to 50 0 C. Ethyl acetate (3 liters) was charged and was heated to reflux for 1 hour under stirring.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel quaternary ammonium salt useful as a potential intermediate in the preparation of amorolfine and its salt. Further the invention also relates to the preparation of the intermediate.
Description
INTERMEDIATE OF AMOROLFINE OR ITS SALT
Field of the Invention
The present invention relates to a quaternary ammonium salt useful as an intermediate in the preparation of amorolfine and its salt. Further, the invention also relates to the preparation of the intermediate.
Background of the Invention
Amorolfine is a morpholine derivative of Formula A,
It is known from U.S. Patent No. 4,202,894, and is used topically as an antifungal agent. It has a broad spectrum of activity, including activity against dermatophytes, various filamentous and dematiaceous fungi, yeasts and dimorphic fungi. GB 1,589,253; EP 0 024 334, EP 0 008 686 and ES 549250 disclose processes for the preparation of amorolfine.
GB 1,589,253 discloses the reaction of 3-(p-tert.amyl-phenyl-2, 3-dimethyl allyl alcohol with phosphorous tribromide in pentane and pyridine to form 3-(p-tert.amyl- phenyl-2, 3-dimethyl allyl bromide. These allyl bromide derivatives have been isolated as a liquid, although with low purity. Also, these allyl bromide derivatives are thermally unstable to distillation. These allyl bromide derivatives get partially decomposed therefore they are carried as such without purification which affects ultimately the purity of amorolfine or its salts.
Summary of the Invention
In one aspect, a novel quaternary ammonium salt, (2E)-3-[4-(l,l-dimethylpropyl) phenyl] -N, N, N-triethyl-2-methylprop-2-ene-l -ammonium bromide of Formula I is provided.
Formula I
In another aspect, a process for the preparation of compound of formula I is provided, comprising reacting 3 -[4-(1,I -dimethyl propyl) phenyl] -2-methylprop-2-ene-l- ol of Formula II
Brief Description of the Drawing Figure 1 is an X-ray diffraction pattern of compound of Formula I.
Figure 2 is a table of peak positions and intensities derived from Figure 1. Detailed Description of the Invention
The compound of Formula I, which is (2E)-3-[4-(l,l-dimethylpropyl) phenyl]-N, N, N-triethyl-2-methylprop-2-ene-l -ammonium bromide is stable and solid, and may be used as a potential intermediate in the preparation of amorolfine or its salts. It may be characterized by its X-ray diffraction pattern, its NMR spectrum or its mass spectrum. It
is solid and crystalline in nature. The crystalline compound of Formula I may be characterized by strong X-ray peaks at about 3.64 ± 0.2 and 14.62 ± 0.2 degrees two-theta. It may also be characterized by additional peaks at about 15.48 ± 0.2, 16.86 ± 0.2, 20.9 ± 0.2, 23.96 ± 0.2, 25.62 ± 0.2, 27.04 ± 0.2 and 27.58 ± 0.2 degrees two-theta. An exemplary X-ray diffraction pattern is provided in Figure 1 , with tabulated peak positions and intensities in Figure 2.
The reaction of a compound of Formula II with phosphorous tri or penta bromide may be carried out in the presence of halogenated hydrocarbons. Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof.
Phosphorous tri or penta bromide may be added to the compound of Formula II in the form of a mixture in halogenated hydrocarbon. The addition may be carried out over about 1 to about 3 hours. The addition of phosphorous tri or penta bromide may be carried out at about -150C to about 15°C. Excess of triethyl amine may be added to the reaction mixture for conversion of a compound of Formula II to a compound of Formula I.
The compound of Formula I may be converted to amorolfine or its salt by the methods known to those skilled in the art, including GB 1,589,253, which is herein, incorporated by reference. In general, it may be prepared by reacting a compound of Formula I with 2,6 dimethyl morpholine followed by hydrogenation and purification to obtain pure amorolfine hydrochloride.
In the following section, particular illustrative embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Reference Example A: Preparation of 3-(p-tert.amyl-phenyI-2, 3-dimethvI allyl bromide
A mixture of 3-(p-tert.amyl-phenyl-2, 3-dimethyl allyl alcohol (50 g) and pyridine (5.0 ml) in n-pentane (350 ml) was cooled to 0 to -5°C. A mixture of phosphorous tribromide (28 g) and n-pentane (350 ml) was added to the above mixture dropwise while
stirring at the same temperature. The reaction mixture was stirred at room temperature for 3.0 hours. The mixture was poured onto distilled water (350 ml) at 0 to -50C slowly and was stirred for 30 minutes. The n-pentane layer was separated and aqueous layer was extracted with n-pentane (100 ml). The combined n-pentane layer was washed with saturated sodium carbonate solution (200 ml) and water (500 ml) and was evaporated to obtain crude 3-(p-tert.amyl-phenyl-2, 3-dimethyl allyl bromide.
Yield: 64.3 g; Chromatographic purity: 80 %; Description: Brown colored oil
Example 1: Preparation of (2EV3-r4-(l J-dimethylpropyl) phenyl! -N. N, N-triethyl-2- methylprop-2-ene- 1 -ammonium bromide :
3-[4-(l,l-dimethyl propyl) phenyl]-2-methylprop-2-ene-l-ol (50g, 0.6870 mol) was dissolved in dichloromethane (250ml) and triethyl amine (24.33g, 0.4808 mol). The reaction mixture was then cooled to 0 to -50C under inert environment. A mixture of phosphorous tribromide (33g) and dichloromethane (165 ml) was added dropwise to the above reaction mixture at 0 to -50C over a period of 2 hours. The reaction mixture was then stirred for 3 hours at 20 to 25°C. The reaction was monitored by TLC or HPLC. After completion of the reaction, distilled water (250 ml) was added, and the mixture was stirred for 15 minutes at 0 to -50C. The organic layer was separated and the aqueous layer was extracted by distilled water (150 ml). The organic layer was again separated at room temperature. The organic layers were combined and washed with distilled water (500 ml). The organic layer was concentrated completely at 30 to 350C to get viscous liquid. The above viscous liquid was suspended with ethyl acetate at 20 to 250C and triethyl amine (24.33g) was added slowly at 20 to 35°C. The reaction mixture was stirred at this temperature for 2 hours. Solid obtained was filtered at room temperature and was washed twice with ethyl acetate (25 ml each) under inert atmosphere. The above wet cake was dissolved in mixture of ethyl acetate (750 ml) and methanol (5.0 ml) and stirred for 10 minutes. Ethyl acetate (255 ml) was recovered at 20 to 25°C. The reaction mixture was cooled to 20 to 250C and stirred for 1 hour at same temperature. The product was filtered, washed with ethyl acetate (50 ml) and dried under reduced pressure at 45 to 5O0C. Dry weight: 42 g; HPLC purity: 99.1%; Description: white colored crystalline powder
1HNMR (CDCIa)5 PPm: 0.653-0.702 (t, 3H); 1.278 (s, 6H); 1.46-1.508 (t, 9H); 1.606- 1.680 (q, 2H); 2.173 (s, 3H); 3.540-3.611 (q, 6H); 4.289 (s, 2H); 6.890 (s, IH); 7.246- 7.273 (d, 2H); 7.320-7.348 (d, 2H).
13C-NMR (CDCl3), ppm: 8.5, 9.0, 20.6, 28.2,36.6, 37.8, 53.5, 67.4, 123.9, 126.0, 129.0, 132.2, 141.0, 149.9.
Mass spectrum: m/z-302.4
Example 2: Preparation of Dehydroamorolfϊne Hydrochloride:
(2E)-3-[4-(l,l-dimethylpropyl) phenyl]-N, N, N-triethyl-2-methylprop-2-ene-l- ammonium bromide (0.35 Kg) obtained above was stirred with toluene (3.5 liters) at room temperature. Cis-2, 6-dimethylmorpholine (0.116 Kg) was added to the above mixture within 20 minutes at same temperature. The reaction mixture was then refluxed at 110 to 112°C for 8 hours. The reaction was monitored by HPLC until the starting material was not more than 1% (w/w). The reaction mixture was then cooled to room temperature and 5% aqueous sodium hydroxide (1.0 liter) was charged. It was stirred for 15 minutes and was allowed to settle for 15 minutes. Distilled water (1.75 liters) was added to the organic layer under stirring. It was stirred for 15 minutes and again was allowed to settle for 15 minutes. The organic layer was separated. It was concentrated under reduced pressure at 55 to 6O0C. The obtained oily residue was cooled to 0 to 50C and 20% methanolic hydrochloric acid (2.1 liters) was added under stirring. The mixture was stirred at this temperature for 1 hour and the temperature was raised to room temperature. Methanol was recovered to maximum extent under reduced pressure at 45 to 500C. Ethyl acetate (2.8 liters) was then added under stirring and the reaction mixture was refluxed for 30 minutes. Ethyl acetate (0.7 liters) was recovered at 79 to 800C. The reaction mixture was cooled at 20 to 25°C and stirred for 1 hour at this temperature. The solid obtained was filtered under nitrogen atmosphere. The wet cake was again mixed with ethyl acetate (1.75 liters) and refluxed for 30 minutes. It was cooled to 20 to 25°C and stirred for 1 hour at this temperature. The solid obtained was filtered under nitrogen atmosphere. The wet solid was dried at 55 to 600C for 15 hours till the moisture was not more than 4.0%. Dry weight: 0.21 Kg; HPLC purity: 99 %
Example 3: Preparation of Crude Amorolfine:
Dehydroamorolfine hydrochloride (0.2 Kg), hydrochloric acid (20 ml) and 10% palladium carbon (20 g, 50% wet) were added in methanol (1.2 liters) at room temperature. Hydrogen gas was purged into the mixture for 3 hours at room temperature. The reaction was monitored by HPLC till dehydroamorolfine was not more than 0.1% (w/w). The reaction mixture was filtered through hyflo bed under nitrogen atmosphere. The hyflo bed was washed with methanol twice (400 ml each). All the filtrates were combined and methanol was recovered under reduced pressure at 45 to 500C. Ethyl acetate (3 liters) was charged and was heated to reflux for 1 hour under stirring. Ethyl acetate (1.4 liters) was recovered at 79 to 8O0C and the mixture was cooled to 0 to 5°C under stirring for 1 hour. The solid was filtered and washed with ethyl acetate twice (100 ml each) under nitrogen atmosphere. The wet solid was dried under reduced pressure at 50 to 600C for 10 hours till the moisture was not more than 1.0% (w/w).
Dry weight: 0.164 Kg; HPLC purity: 99.2 %
Example 4: Preparation of Pure Amorolfine:
Crude amorolfine hydrochloride (0.15 Kg) was stirred with dichloromethane (0.75 liters) at room temperature. The mixture was filtered through hyflo and hyflo bed was washed with dichloromethane twice (225 ml each). All the filtrates were combined and dicloromethane was recovered under reduced pressure at 30 to 35°C. Ethyl acetate (1.5 liters) was charged and was heated to reflux for 1 hour under stirring. Ethyl acetate (450 ml) was recovered at 79 to 800C and the mixture was cooled to 20 to 25°C under stirring for 1 hour. The solid was filtered and washed with ethyl acetate twice (75 ml each) under nitrogen atmosphere. The wet solid was dried under reduced pressure at 55 to 600C for 20 hours till the moisture was not more than 1.0% (w/w).
Dry weight: 0.135 Kg; HPLC purity: 99.8 %
Claims
WE CLAIM: 1. A compound of Formula I,
Formula I 2. A crystalline compound of Formula I, characterized by strong X-ray peaks at about 3.64± 0.2 and 14.62 ± 0.2 degrees rwo-theta and additional peaks at about 15.48± 0.2, 16.86± 0.2, 20.9± 0.2, 23.96± 0.2, 25.62± 0.2, 27.04± 0.2 and 27.58± 0.
2 degrees two- theta.
3. A process for the preparation of a compound of formula I
Formula I comprising reacting 3 -[4-(1,I -dimethyl propyl) phenyl]-2-methylprop-2-ene-l-ol of Formula II
4. The process according to claim 3 wherein the reaction of compound of formula II with phosphorous tri or penta bromide is carried out in the presence of halogenated hydrocarbons.
5. The process according to claim 4 wherein halogenated hydrocarbons selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof.
6. The process according to claim 3 wherein phosphorous tri or penta bromide is added to the compound of Formula II in the form of a mixture in halogenated hydrocarbon.
7. The process according to claim 3 wherein the addition of phosphorous tri or penta bromide is carried out within the duration of about 1 to about 3 hours.
8. The process according to claim 3 wherein the addition of phosphorous tri or penta bromide is carried out at about -15°C to about 15°C.
9. The process according to claim 3 wherein excess of triethyl amine is added to the reaction mixture for conversion of compound of formula II to Compound of Formula I.
10. Use of compound of Formula I, as prepared in claim 3, for the preparation of amorolfme or its salts.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN41DE2005 | 2005-01-07 | ||
| IN41/DEL/2005 | 2005-01-07 |
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| Publication Number | Publication Date |
|---|---|
| WO2007000628A1 true WO2007000628A1 (en) | 2007-01-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IB2006/000022 WO2007000628A1 (en) | 2005-01-07 | 2006-01-09 | Intermediate of amorolfine or its salt |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010094739A1 (en) * | 2009-02-20 | 2010-08-26 | Synteco S.P.A. - Prodotti Di Sintesi Per L'industria Chimica E Farmaceutica | Process for the purification of amorolfine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4202894A (en) * | 1976-11-22 | 1980-05-13 | Hoffmann-La Roche Inc. | Piperidines morpholines, etc., and fungicidal compositions thereof |
| GB1591267A (en) * | 1976-12-15 | 1981-06-17 | Basf Ag | Morpholine derivatives and their use as fungicides |
-
2006
- 2006-01-09 WO PCT/IB2006/000022 patent/WO2007000628A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4202894A (en) * | 1976-11-22 | 1980-05-13 | Hoffmann-La Roche Inc. | Piperidines morpholines, etc., and fungicidal compositions thereof |
| GB1591267A (en) * | 1976-12-15 | 1981-06-17 | Basf Ag | Morpholine derivatives and their use as fungicides |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010094739A1 (en) * | 2009-02-20 | 2010-08-26 | Synteco S.P.A. - Prodotti Di Sintesi Per L'industria Chimica E Farmaceutica | Process for the purification of amorolfine hydrochloride |
| CN102325572A (en) * | 2009-02-20 | 2012-01-18 | 辛特克股份公司 | Process for the purification of amorolfine hydrochloride |
| US8664381B2 (en) | 2009-02-20 | 2014-03-04 | Synteco S.P.A. | Process for the preparation and purification of amorolfine hydrochloride |
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