| WO/1999/007360 | COMPOUNDS AND USES THEREOF |
VENKIAH CHOWDARY NANNAPANENI (IN)
RAJASEKHARA REDDY PEDDI (IN)
PULLA REDDY MUDDASANI (IN)
VENKIAH CHOWDARY NANNAPANENI (IN)
RAJASEKHARA REDDY PEDDI (IN)
| US5817875A | 1998-10-06 |
| 1. | An improved process for the preparation of the compound of the formulaI, a key intermediate used in the preparation of terbinafine of the formula11, which comprises: (i) Preparing 3, 3dimethyl1butynylmagnesium halide by treating tertbutyl acetylene with lower alkymagnesium halide in an etherhydrocarbon solvent mixture at a temperature in the range of5°C to 0°C. (ii) Adding the epoxy compound of the formulaIV, IV to the resulting acetylenic Grignard reagent at a temperature in the range of 30°C to 0°C (iii) Slowly heating the reaction mixture to reflux temperature of the solvent employed in the reaction (iv) Quenching the reaction mass with saturated ammonium chloride (v) Filtering the reaction mass to remove the magnesium salts (vi) Distilling of the solvent and isolating the compound of the formulaI and (vii) Simple crystallizing from a nonpolar hydrocarbon solvent to get the pure compound f of the formula I. |
| 2. | An improved process as claimed in claim 1 wherein the lower alkyl magnesium halide employed in step (i) of the reaction is selected from methylor ethylmagnesium bromide or iodide, preferably methylmagnesium iodide or ethylmagnesium bromide. |
| 3. | An improved process as claimed in claims 1 & 2 wherein the ether solvent used in step (i) is selected from diethyl ether, diisopropyl ether, methyl tertbutyl ether, tetrahydrofuran, 1,4dioxane, preferably, tetrahydrofuran or diethyl ether. |
| 4. | An improved process as claimed in claims 1 to 3 wherein the hydrocarbon solvent used in step (i) is selected from hexane, heptane, cyclohexane, toluene, preferably hexane or toluene. |
| 5. | An improved process as claimed in claims 1 to 4 wherein the temperature used in step (ii) ranges between10°C to30°C, preferably15°C to25°C, more preferably20°C. |
| 6. | An improved process as claimed in claims 1 to 5 wherein the rate of heating of reaction mass in step (iii) ranges between 3060min to reach 0°C, preferably 5060min. |
| 7. | An improved process as claimed in claims 1 to 6 wherein the rate of heating of reaction mass in step (iii) ranges between 3060min to reach 25°C, preferably 3045min. |
| 8. | An improved process as claimed in claims to claim 1 to 7 wherein the rate of heating of reaction mass in step (iii) ranges between 3060min to reach 6570°C, preferably 45 60min. |
| 9. | An improved process as claimed in claims 1 to 8 wherein the solvent used for crystallization of the compound of the formulaI is selected from hexane, heptane, cyclohexane, diisopropyl ether, toluene, or mixture thereof preferably a mixture of hexane/toluene. |
| 10. | An improved process for the preparation of the compound of formulaI substantially as described in Examples 1 to 3. |
I Terbinafine (II) BACKGROUND OF INVENTION The compound of the formula-I is reported for the first time in Canadian patent no 2, 185, 599 and subsequently in US patent no 5,817, 875. This compound is dehydrated under various conditions to get a mixture of E and Z-terbinafine in various ratios depending upon the conditions employed.
According to the process disclosed in the above Canadian and US patents N-methyl-N- naphthylmethylamine of the formula-III is reacted with excess of epichlorohydrin in the presence of a base to get the epoxy compound of the formula-IV (Scheme-1). Surprisingly the epoxy compound of the formula-IV was not found to be reactive towards lithium tert- butylacetylene in an inert solvent like THF. To overcome this problem borontrifluoride- etherate was used in the reaction, which required-78°C. Also, the process requires butyl lithium in making lithium tert-butylacetylene. After the usual water workup the compound of formula-I was isolated in crude form. The crude compound of the formula- I was purified by column chromatography to isolate it as an oil.
Scheme-I The main drawback in this process is that it requires a Lewis acid like borontrifluoride- etherate, which is corrosive and requires special handling on a plant scale. Handling of n- butyl lithium in making the lithium tert-butylacetylene is not economically viable on commercial scale. Also, the reagent is highly flammable and requires special handling in transport as well as in use. Although the yield claimed in the above process is 79%, it required one column chromatography, which is not suitable on plant scale operations. All these things make the process not commercially attractive.
SUMMARY OF INVENTION During our sustained research on developing a commercially viable process for the preparation of the compound of the formula-I, we realized that avoidance of (i) reaction at a temperature as low as-78°C (ii) handling of n-butyl lithium (iii) handling of borontrifluoride-etherate and (iv) the usage of column chromatography would be beneficial. We also observed that the compound of the formula-I could be readily crystallized from a non-polar hydrocarbon solvent.
Keeping in view of the difficulties in implementing the reported conditions for the preparation of the compound of the formula-I, we turned our attention towards developing simple conditions and reagents to make the compound of the formula-I.
According to the literature (L. Brandsma & H. D. Verkruijsse, Synthesis of acetylenes, allenes and cumulenes, Elsevier 1981, p 17-18) available on acetylenic compounds Grignard reagents derived from acetylenic compounds are reactive enough towards epoxides under normal conditions. Also preparation of these acetylenic Grignard reagents is easy and will not require any low temperature or hazardous conditions. Based on this information and on our realizing the avoidance of the above reactions conditions and reagents, we were successful in developing an improved process for the preparation of the compound of the formula-I.
Therefore the main objective of the present invention is to provide an improved process for the preparation of the compound of the formula-I, which is a key intermediate for the preparation of terbinafine of the formula-11, which is simple, economical and commercially viable.
Another objective of the present invention is to provide an improved process for the preparation of the compound of the formula-I, which is a key intermediate for the preparation of terbinafine of the formula-11 avoiding the temperature as low as-78°C for the reaction.
Still another objective of the present invention is to provide an improved process for the preparation of the compound of the formula-I which is a key intermediate for the preparation of terbinafine of the formula-11 avoiding the use of n-butyl lithium in the reaction thereby making the process simple and user friendly.
Yet another objective of the present invention is to provide an improved process for the preparation of the compound of the formula-I, which is a key intermediate for the
preparation of terbinafine of the formula-II avoiding the use of borontrifluoride-etherate thereby making the process further simple and user friendly.
Another objective of the present invention is to provide an improved process for the preparation of the compound of the formula-I, which is a key intermediate for the preparation of terbinafine of the formula-il avoiding the usage of column chromatography again making the process simple.
Still another objective of the present invention is to provide an improved process for the preparation of the compound of the formula-I, which is a key intermediate for the preparation of terbinafine of the formula-11 employing simple crystallization process using a non-polar hydrocarbon solvent to get a pure compound of the formula-I.
Accordingly, the present invention provides an improved process for the preparation of the compound of the formula-I,
a key intermediate used in the preparation of terbinafine of the formula-11, which comprises:
(i) Preparing 3, 3-dimethyl-l-butynylmagnesium halide by treating tert-butyl acetylene with lower alkyl magnesium halide at a temperature in the range of -5°C to 0°C (ii) Adding the epoxy compound of the formula-IV IV to the resulting acetylenic Grignard reagent of step (i) at a temperature in the range of 0°C to-30°C (iii) Slowly heating the resulting reaction mixture to the reflux temperature of the solvent employed in the reaction (iv) Quenching the reaction mass with saturated ammonium chloride (v) Filtering the reaction mass to remove the magnesium salts and (vi) Distilling of the solvent and (vii) isolating the compound of the formula-I by simple crystallization from a non- polar hydrocarbon solvent.
From the above defined process it would be observed that the process (i) avoids the usage of hazardous reagent like butyl lithium making the process user friendly, (ii) avoids the usage of borontrifluoride etherate, thereby making the process not only economical but also environment friendly pollutant (iii) avoids the usage of column chromatography thereby making the process commercially feasible and simplifying the purification of the compound of formula-I and (iv) isolating the compound of formula-I as a crystalline solid. Such a process for the preparation of compound of the formula I is not hitherto known and therefore it is a novel process. Accordingly the process developed and defined above is a novel process.
In a preferred embodiment of the present invention, 3, 3-dimethyl-l-butynylmagnesium halide is prepared by treating tert-butylacetylene with lower alkylmagnesium halide in solvents preferably, ether such as THF, diethyl ether, 1, 4-dioxan alone or in combination with non-polar solvent such as toluene, cyclohexane, heptane, hexane, etc., The lower alkymagnesium halide required in the conversion of tert-butylacetylene into its magnesium derivative is methylmagnesium bromide or iodide, ethylmagnesium bromide or iodide, etc, preferably ethylmagnesium bromide. Temperature of the reaction can be between-5°C to 25°C. Addition of the compound of the formula-IV to 3, 3-dimethyl-l- butynylmagnesium halide should be done at 0°C to-20°C, preferably at-1 S°C to-20°C.
After the addition of the compound of the formula-IV to 3, 3-dimethyl-1- butynylmagnesium bromide the reaction mass should be slowly heated to reflux temperature (between 50°C-70°C). The rate of heating to reflux temperature should be in such a way that it takes at least 4-6hrs to reach reflux temperature.
Workup of the reaction should be done by adding saturated ammonium chloride to the reaction mass, preferably at 0-30°C. The amount of saturated ammonium chloride should be on a molar basis to the amount of Grignard reagent used in the reaction, preferably 1.5 to 2.0 equivalents. This will avoid the water workup and the product can be directly isolated from the reaction mass by simple filtration and distillation of solvent.
Purity of the crude compound of formula-I prepared according to the present invention was found to be 85 to 90% by HPLC. This is sufficiently pure enough for further conversion to terbinafine of formula-II. However, it can be crystallized from solvents like pentane, hexane, heptane, cyclohexane, or a mixture of these solvents with diisopropyl ether. Isolated compound of the formula-I melted at 52°C.
The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example.
Example 1 Preparation of N-methyl-N- (1-naphthylmethyl)-6, 6-dimethyl-2-hydroxyheptan-4- ynyl-1-amine of the formula-I A solution of tert-butylacetylene (58gr) in THF (58ml) was slowly added to a solution of ethylmagnesium bromide (prepared from 15.4gr of magnesium and 70gr of ethyl bromide) in THF (270ml) at 0-5°C over a period of 2hrs. The reaction mixture was maintained at same temperature for lhr and slowly raised to 25-30°C. After maintaining for 2hrs at 25°-30°C, the reaction mixture was cooled to-15°C and a solution of the epoxy compound (lOOgr) in hexane (50ml) and 100ml THF was added to the reaction mixture over a period of 2hrs. The reaction mixture was maintained for 30min at this temperature and slowly raised to 0°C over a period of 45min. The temperature of the reaction mass was raised to reflux (60-65°C) over a period of lhr and maintained at reflux for 6hrs. TLC of the reaction showed the absence of starting epoxy compound. The reaction mixture was cooled to 5-10°C and added aqueous ammonium chloride (15gr dissolved in 130ml water) over a period of 1hr keeping the temperature below 15°C. The reaction mixture was stirred at 25°C for 3hrs and filtered on a hi-flow bed. The hi-flow bed was washed with 100ml of toluene. Solvent was distilled off from the filtrate under reduced pressure to get the crude title compound (134gr) as syrup. Hexane (150ml) was added to the residue and kept under stirring at 5-10°C for 2hrs. The mass was further cooled to-5 to 0°C and maintained for 2hrs before filtration. The resulting compound was dried under vaccum to get white crystals (lOOgr) of N-methyl-N-(l-naphthylmethyl)- 6, 6-dimethyl-2-hydroxyheptan-4-ynyl-1-amine of the formula-1. Melting point is 52°C.
Example 2 Preparation of N-methyl-N- (1-naphthylmethyl)-6, 6-dimethyl-2-hydroxyheptan-4- ynyl-t-amine of the formula I A solution of tert-butylacetylene (60gr) in THF (60ml) was slowly added to a solution of ethylmagnesium iodide (prepared from 15. 5gr of magnesium and lOOgr of ethyl iodide) in THF (300ml) at 0-5°C over a period of 2hrs. The reaction mixture was maintained at same temperature for Ihr and slowly raised to 25-30°C. After maintaining for 2hrs at 25°C, the reaction mixture was cooled to-15 to-20°C and a solution of the epoxy
compound (lOOgr) in toluene (50ml) was added to the reaction mixture over a period of 2hrs. The reaction mixture was maintained for 15-20min at this temperature and slowly raised to 0°C over a period of Ihr. The temperature of the reaction mass was raised to reflux (60-65°C) over a period of 2hrs and maintained at reflux for 6hrs. TLC of the reaction shows the absence of starting epoxy compound. The reaction mixture was cooled to 5-10°C and added aqueous ammonium chloride (15gr dissolved in 300ml water) over a period of lhr keeping the temperature below 15°C. The reaction mixture was stirred at 25°C for 3hrs and filtered on a hi-flow bed. The hi-flow bed. was washed with 100ml of toluene. Solvent was distilled off from the filtrate under reduced pressure to get the crude title compound (133gr) as syrup. Hexane (100ml) was added to the residue and kept under stirring at 5 to 10°C for 2hrs. The mass was further cooled to-5 to 0°C and maintained for 2hrs before filtration. The compound was dried under vaccum to get white <BR> <BR> crystals (103gr) ofthe N-methyl-N-(l-naphthylmethyl)-6, 6-dimethyl-2-hydroxyheptan-4- ynyl-1-amine of the formula-1.
Example 3 Preparation of N-methyl-N- (1-naphthylmethyl)-6, 6-dimethyl-2-hydroxyheptan-4- ynyl-1-amine of the formula I A solution of tert-butylacetylene (58gr) in THF (60ml) was slowly added to a solution of methylmagnesium iodide (prepared from 15. 5gr of magnesium and 92gr of methyl iodide) in THF (300ml) in THF at 0-5°C over a period of 2hrs. The reaction mixture was maintained at same temperature for lhr and slowly raised to 25 to 30°C. After maintaining for 2hrs at 25°C the reaction mixture was cooled to-20 to-25°C. A solution of the epoxy compound (lOOgr) in toluene (100ml) was added to the reaction mixture over a period of 2hrs below-20°C. The reaction mixture was maintained for 15-20min at this temperature and slowly raised to 0°C over a period of lhr. The temperature of the reaction mass was raised to reflux (60 to 65°C) over a period of 2hrs and maintained at reflux for 5hrs. TLC of the reaction shows the absence of starting epoxy compound. The reaction mixture was cooled to 5 to 10°C and added aqueous ammonium chloride (20gr dissolved in 300ml water) over a period of lhr keeping the temperature below 15°C. The
reaction mixture was stirred at 25°C for 3hrs and filtered on a hi-flow bed. The hi-flow bed was washed with 100ml of toluene. Solvent was distilled off from the filtrate under reduced pressure to get the crude title compound (130gr) as syrup. Hexane (100ml) was added to the residue and kept under stirring at 5 to 10°C for 2hrs. The mass was further cooled to-5 to 0°C and maintained for 2hrs before filtration. The compound was dried under vaccum to get white crystals (lOOgr) of N-methyl-N- (1-naphthylmethyl)-6, 6- dimethyl-2-hydroxyheptan-4-ynyl-1-amine of the formula-I.
Advantages of the invention 1. The process is simple and easily adaptable for the commercial production of the compound of the formula-I.
2. The process avoids the use of (i) a temperature as low as-78°C (ii) n-butyl lithium (iii) borontrifluoride-etherate and (iv) column chromatography making the process user and environment friendly and economical.
3. The compound of the formula-I can be readily crystallized from a non-polar hydrocarbon solvent to give the pure compound.