WO2005110968A1

WO2005110968A1 - An improved process for the preparation of terbinafine hydrochloride

Info

Publication number: WO2005110968A1
Application number: PCT/IN2005/000157
Authority: WO
Inventors: Rajender Prashad Gupta; Kaku Vijay Sekhar Reddy
Original assignee: Hydex Chemicals Pvt Ltd.
Priority date: 2004-05-14
Filing date: 2005-05-13
Publication date: 2005-11-24

Abstract

The present invention relates to an improved process for preparation of terbinafine hydrochloride ,which is (E) - N- Methyl -N-(1-Naphtylmethyl)-6,6-dimethylhept-2-ene-4-ynyl-1-amine has the formula (I), which comprises reacting t-butylacetylene with ethylmagnesium bromide in THF (ii) adding acrolein at a temperature in the range of 0-10o C to get , 6,6-dimethyl-hept-1-ene-4-yne-3-ol, (iii) reacting it with a mixture of phosphorous oxychloride and hydrochloric acid in methanol (iv) extracting the reaction mass with aliphatic/aromatic solvent & removing the solvent (v) reacting the residue with N-(1-naphtylmethyl)methyl amine in the presence of a base to give Terbinafine (vi) adding hydrochloric acid and extracting the Terbinafine Hcl formed with a chlorinated solvent and (vii) recovering the chlorinated solvent under vacuum and adding ethylacetate to separate Terninafine hydrochloride which is filtered and dried.

Description

IMPROVED PROCESS FOR THE PREPARATION OF TERBINAFINE HYDROCHLORIDE.

BACK GROUND OF THE INVENTION

The present invention relates to an improved process for preparation of terbinafine hydrochloride. Terbinafine hydrochloride which is (E) - N- Methyl -N-(l-

Naphtylmethyl)-6,6-dimethylhept-2-ene-4-ynyl-l-arnine has the formula (I).

1 The invention also includes the process for the preparation of Terbinafine hydrochloride. Terbinafine of the formula (I) was reported first in the European patent No.24587, as a good antifungal agent used preferably against mycosis caused by dermathophytons on the skin and on the nail. This compound was prepared in three different ways, according to the process disclosed in this patent . It is obtained in base form - namely mixture of cis (Z) and trans (E) isomers. Tert. butyl actylene is converted to 6,6-dimethylhept-l-ene-4- yne-3-ol using n-butyllithium at -70°C. Reaction of this intermediate with HBr and then condensation of this bromo derivative with N-(l-Naphthylmethyl) methylamine gave a mixture of Cis(Z) and Trans(E) Terbinafine. The separation of this mixture was achieved by column chromatography. The drawbacks of this process is the employment of column chromatography for the separation which is not preferably used on industrial large-scale production. Further the process uses n-butyl lithium, which is difficult to handle on industrial scale. In a later publication (J. Med. Chem 27, 1539-1543 (1984) the hydro chloride salt of the trans (E) isomer of Terbinafine was prepared from the mixture of Cis (Z) and Trans (E) by column chromatography on silica gel and salt formation of base by treatment with hydrochloric acid in ethanol followed by recrystallization. Tert. Butyl acetylene is converted to 6,6 dimethylhept-l-ene-4-yne-3-ol using n-butyllithium and acrolein at-70C. This method is not favorable for industrial scale production because of the use of n- butyllithium at low temperature which is not safe on industrial scale and also the use of column chromatography .

After the success of Terbinafine on the market as a good antifungal agent used on the preferably against mycosis caused by dermathophytons skin and on the nail many processes for its preparation have been published. Few of the important ones are discussed below

Li the process disclosed in the Swiss patent no. 678527, the hydrochloride salt of N-(l- Naphthylmethyl) methylamine of the formula (H) and geometric isomeric (E:Z) mixture of (3:1) of l-bromo-6,6-dimethyl -hept-2-ene-4-yne of the formula (HI a) used as starting materials.

ii m

The secondary amine of the formula (II) is alkylated by bromo compound of the formula (Dla) in the presence of aqueous sodium hydroxide. The terbinafine base was formed as the mixture (E) and (Z) isomers as an oily substance. The crude Terbinafine (still a mixture of isomers) obtained by extraction with toluene and by evaporation of toluene, has the same geometric isomeric ratio of 3:1 (E:Z) mixture as the compound of the formula (flla). The crude terbinafine was dissolved in ethyl acetate and hydrogen chloride gas was introduced in to the solution. After a long time (4-15hrs.)of stirring the precipitated hydrochloride salt of trans terbinafine product of formula(T) was centrifuged, washed with ethyl acetate and dried.

The disadvantage of the process is that it gives lower yield ( 50% ) . On our repeating the process as explained above observed that complete conversion of the base in ethyl acetate to its hydrochloride salt by purging HC1 gas does not lake place and hence resulting in the lower yields. Canadian Patent no 2,185599 describes a process for the preparation of terbinafine by reaction of secondary amine of the formula (II) with an excess of epichlorohydrin to give epoxide of the formula (TV)

(IV) The epoxide of the formula (TV) is converted to secondary alcohol of the formula V and with its dehydration, a mostly undefined geometric isomeric mixture of the formula (I) was obtained . The process have the following disadvantages.

1 Large excess of epichlorohydrin is used. (9.9 mole as against 0.45mole required)

2. n-Butyl lithium is used which is not safe to handle on industrial scale.

3. The secondary alcohol formed after the epichlorehydrin reaction stage, on dehydration gives mixture of cis (Z) and Trans(E) isomers. As a result Trans(E) form of Terbinafine is obtained with at most 50% yield.

In another process disclosed in the US Patent No. 5440049 secondary amine of the formula (H.) is reacted with 1,3-dichloropropene cis(Z):Trans(E) 1:9 to give vinylchloride of formula (V)

(V) Which is condensed with tert-butylacetylene using Pd catalyst.

The above process employs trans- 1 ,3-dichloropropene which is highly expensive therefore increases the production cost of the final product. Further the process employs expensive Pd catalyst and the process is too complicated because of the following reasons 1) Preparation and purification of Trans 1,3 dichlopropene from the mixture of cis & trans isomers is lengthy and expensive. The boiling point of cis and trans isomers of 1 ,3- dichloropropene are very close (difference of 2-3°c). More over the distillation polymerises 1,3-dichloropropene.

2) It employs pd catalyst which lengthy to make, recover and recycle. It is expensive, hence not economical on industrial scale.

The process disclosed in the Korean laid open Patent No. 2000-65,691 involves condensation of secondary amine of the formula (H) hydrochloride salt and mixture (cis/trans=l/l) of 1,3-dichloropropene in the presence of Pd catalyst to give vinyl chloride cis/trans as given in the formula (VI)..

(VI) The mixture of cis/trans is reacted with tert-butylacetylene in the presence of Pd catalyst to give terbinafine. This process employs cis/trans mixture of 1,3-dichloropropene in order to improve the process US Patent No. 5440049. This process too is complex as Pd catalyst is employed twice and the process is not economical.

E (Trans) (VII) Z (CIS)

The process disclosed in US Patent No. 5819875 involves reaction of secondary amine hydrochloride of the formula II and epichlorohydrin to give epoxide of the formula (TV). This epoxide is reacted with tert- butylacetylene in the presence of n-butyl lithium and further reaction with borontrifluoride etherate at 70°C to give secondary alcohol of the formula (V). The secondary alcohol on reaction with methanesulfonyl chloride and methylamine and further reaction with DBU gives Terbinafine. This process is also not economically feasible because of the use of n- butyl lithium due to cost and handling on industrial scale. The other reaction are also complicated.

US Patent No. 6515181 describes a process which involves reaction of secondary amine of the formula (H) with (E) 1,3-dichloropropene to vinyl chloride of the formula (VI). The vinylchloride is converted to terbinafine HCl on reaction with tert butyl acetylene and copper iodide.

The production of vinylchloride of the formula (VI) is expensive due to the use of expensive (E) 1 ,3-dichloropropene.

WO 01/28976 describes a process involving the reaction of 6,6-dimethyl-hept-l-ene-4- yne-3-ol with hydrochloric acid and subsequent reaction of mixture (cis/trans) 1-chloro- 6,6-dimethyl-hept-2-ene-4-yne in methyl isobutyl Ketone with secondary amine of the formula (IT) to give Terbinafine which is converted to its hydrochloride salt in methyl isobutyl ketone. The yields reported are low (38% to 53%) hence process is not economical.

US patent No. 6570044 describes the preparation of 6,6-dimethyl-hept-l-ene-4-yne-3-ol by reaction of ethylmagnesiumbromide with tert-butyl acetylene and further reaction of tert-butylacetylide formed with acrolein . The preparation of grignard reagent ethymagnesium bromide is done using a mixture of toluene:THF (9:1) and also the further reactions. The mixture of toluene and THF give insoluble grignard reagent hence the yield is low (48%).

US Patent No. 6,689,913 published in Feb, 2004 describes a process which comprises reaction of 2-pivaloylfuran with hydrazide compounds to give hydrazone derivative . This hydrazone derivative on reaction with secondary amine and further reduction with sodium borohydride and converting the base with hyd ochloric acid gives Terbinafine HCl The yield are very low ranging form 9.0% to 44%. The process is lengthy and not economical.

Due to the success of Terbinafine in the market as a good antifungal agent particularly against mycosis caused by dermathophytons on the skin and on the nail many felt a necessity to develop an improved process overcoming the disadvantages of the above said prior art processes which process will also be useful for commercial manufacture of Terbinafine hydrochloride.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is , therefore , to provide an improved process for the preparation of Terbinafine hydrochloride over coming the drawbacks the hitherto known prior art processes. Another objective of the present invention is to provide an improved process for the preparation of Terbinafine hydrochloride which is economical.

Still another objective of the present invention is to provide an improved process for the preparation of Terbinafine hydrochloride which is simple using commonly available raw materials Yet another objective of the present invention is to provide an improved process for the preparation of Terbinafine hydrochloride in one pot reaction which can be employed commercially.

As seen from the prior art process disclosed in the US Patent No.6570044 preparation of

6,6-dimethyl-hept-l-ene-4-yne-3-ol, is carried out by reaction of ethyl magnesiumbromide .prepared by reaction of ethylbromide with magnesium in a mixture of toluene and THF

(90% toluene in THF) and further reaction with acrolein at 0-5°C. The yield obtained is only 48% . 6,6-dimethyl -hept-l-ene-4-yne-3-ol is used as an intermediate in the preparation of Terbinafine hydrochloride.

We have been doing similar reaction since 1999 for the manufacture of 6,6-dimethyl-hept- l-ene-4-yne-3-ol which , as stated above , is an intermediate for the preparation of Terbinafine hydrochloride. This process employs a single solvent namely THF in which grignard reagent is soluble and our yield of 6,6-dimethyl-hept-l-ene-4-yne-3-ol is 65% as compared to 48% reported in US Patent No.6570044.

In our process according to the present invention the Grignard reagent used namely , ethyl magnesium bromide , is prepared in THF by reaction of ethylbromide with magnesium followed by addition of tert-butyl acetylene at 0-5° C and then final addition of acrolein at a temperature in the range of 0-10° C. The reaction mixture on workup gives 6,6-dimethyl-hept-l-ene-4-yne-3-ol in 65% yield with purity of 97+2%. Since only a single solvent , namely THF , for the preparation of grignard reagent ethylmagnesiumbromide is used which is followed by addition of tert-butyl acetylene at 0-5°C and final addition of acrolein at 0-10°C, higher yield (65%) of 6,6-dimethyl-hept-l- ene-3-ol after workup against reported yield of 48% is obtained . The increase in the yield according to the process of the present invention , may perhaps be attributed to the less solubility of Grignard reagent ethylmagnesium bromide in the mixture of toluene and THF.

The present invention involves the conversion of 6,6-dimethyl-hept-l-ene-4-yne-3-ol to Terbinafine hydrochloride in one pot without isolation of any intermediates.

Accordingly, the present invention provides an improved process for the preparation of Terbinafine hdrochloride which comprises (i) reacting t-butylacetylene with ethylmagnesium bromide in THF followed by addition of acrolein at a temperature in the range of 0-10° ^c to get , 6,6- dimethyl-hept-1 -ene-4-yne-3-ol. (ii) reacting the resulting 6,6-dimethyl-hept-l-ene-4-yne-3-ol with a mixture of phosphorous oxychloride and hydrochloric acid in methanol. (iii) extracting the reaction mass with aliphatic/aromatic solvent, (iv) removing the solvent under vacuum to give a residue. (v) reacting the residue obtained with N-(l-naphtylmethyl)methyl amine in the presence of a base to give Terbinafine. (vi) adding hydrochloric acid and extracting the Terbinafine Hcl formed with a chlorinated solvent and (vii) recovering the chlorinated solvent under vacuum and addition of ethylacetate to separate Terninafine hydrochloride which is filtered and dried. Detailed description of Invention In the first step ethyl magnesium bromide is prepared by the reaction of ethyl bromide and magnesium in THF followed by addition of tert-butylacetylene, ethane gas is evolved and tert-butyl acetylide is formed. The reaction is carried out at reflux temperature up to 75°c for several hours preferably 2 to 5 hours . Tert-butyl acetylide formed is reacted with acrolein at 0-10°c to give 6,6-dimethyl -hept-l-ene-4-yn-3-ol in high yield ( > 65%) with purity of 97±2%.

This intermediate 6,6-dimethyl-hept-l-ene-4-yne-3-ol is reacted with phosphorousoxychloride, hydrochloric acid in methanol. The resultant reaction mixture is extracted with aliphatic/aromatic hydrocarbon. The hydrocarbon is selected from n- hexane, cyclohexane , benzene, toluene, xylene, more preferably n-hexane. The solvent is recovered under vacuum to give residue which is analysed. The residue is reacted with N- (l-napthylmethyl)amine in presence of base( inorganic/organic) without any solvent. The base is selected from caustic soda, caustic potash, sodium carbonate, sodium bicarbonate etc., triethylamine ,diethylamine,etc. more preferably caustic soda. The completion of the reaction is checked on Tic and proceeded further.

The reaction mixture is diluted with hydrochloric acid and extracted with chlorinated solvent. The chlorinated solvent is selected from methylene chloride, ethylene dichloride, chloroform, more preferably methylene chloride. The solvent is recovered under atmospheric pressure and traces are removed under vacuum to give residue containing Terbinafine hydrochloride.Ethylacetate is added to the residue containing Terbinafine hydrochloride. The separated product is filtered and dried to give Terbinafine hydrochloride in yield of > 81-0% based on the purity of the residue with HPLC purity > 99.9%.

The details of the invention are given in the Examples given below which are provided to illustrate the invention and therefore should not be construed to limit the scope of the invention .It fully understood and appreciated that it is intended to cover all the alternatives, modifications and equalities as may be included with in the scope of the invention Example 1 In a four necked 2 Lit round bottom flask fitted with overhead mechanical stirrer, double surface condenser, thermometer pocket, and pressure equalizing funnel placed in the plastic tub, top of the condenser is connected with nitrogen inlet, THF 300ml, magnesium turnings (29.0grm. 1.208moles.) were charged . The flow of nitrogen was started and small amount (crystal) of iodine approximately 50.0 mgs. and 5ml of ethyl bromide was charged .The reaction starts with disappearance of brownish color,. Ethyl bromide (133.0grm. 1.22 moles) mixed with THF (50ml ) were charged in pressure equalizing tunnel and started the addition of ethyl bromide slowly. The reaction flask was cooled with ice water and the temperature was maintained at 25-30°c. The cooling bath was replaced with water bath after the ethyl bromide addition was completed. The temperature was raised slowly up to 73-75°c. The reaction mixture was kept under reflux for 1 to 2 hours. The water bath was removed and the reaction flask was kept in a cooling bath replacing the condenser .with nitrogen inlet. The reaction mass was cooled to 0-5°c and t-butylacetylene (lOOgrm. 1.219 moles) mixed with THF (50ml) was charged through the funnel. The addition of t-butyl acetylene was started slowly at 0-5°c with stirring for some time at 0-5°c. Arolein (68.0grm 1.22moles) mixed with THF (50ml) was charged through the fiinnel. The reaction mass was kept at 0-5°c, and stirred further for 2 to 3 hours at the same temperature and the temperature was raised to room temperature and stirred - for 18 to 20 hours and checked the completion of the reaction on gas chromatography. The reaction mixture is quenched with dil HCl and water, and the pH was adjusted to 2 to 2.5. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic phase is washed with water to neutrality. The organic phase is dried and solvent stripped to give 6,6-dimethyl-hept-l-ene-4-yne-3-ol in 65.4% yield with purity of 97.2% . This is dissolved in methanol (300ml) and cooled to 0-5°C and mixture of phosphorous oxychJoride (35.0grm 0.33mole), Hydrochloric acid (300ml) is charged slpwly at 0-5°c. The reaction mixture was stirred at 0-5°c for 2 to 4 hours and the temperature was raised to roorfi temperature arid further stirred for several hours 18 to 20 hours . The completion of the reactiόti is chfeckecj oϋ g-tø

After me reaction is completed,- n-hexane (300ml) was charged , stirred for 30 min, and the phases were separated. The aqueous phase was re-extracted with n-hexane (100ml) and the combined organic phase was washed with water to neutrality. The organic solvent was stπpped and to the residue, N'-(l-napthylmethyl) methylamine and caustic soda flakes are charged . The reaction mixture was heated up to 80°c and maintained at this temperature until reaction is completed. The reaction mass is cooled to room temperature and hydrochloric acid (400ml), methylene chloride 400ml are charged and stirred . The phases are separated, the organic-phase washed with water until neutrality. The methylene chloride was recovered and ethyl acetate is added. The separated Terbinafine HCl is filtered and ashed with_^eώyl acet te and dried to give 134 grm (81% yielά o tejbiBafine hydrochloride with 99% of purity having no cis (Z) isomer.

• Advantages ot the present invention

1. T-he process involves one pot reaction from fert^Butyl acetylene to Terbinafine hydrochloride , thereby making the process simple and economical

2. The purity of Terbinafine hydrochloride produftød^'is >99.9 % and yield>81% 3. The process is^appljcabl^ commercially.

Claims

1 An improved process for the preparation of Terbinafine hdrochloride which comprises (i) reacting t-butylacetylene with ethylmagnesium bromide in THF followed by addition 5 of acrolein at a temperature in the range of 0-10°c to get , 6,6-dimethyl-hept-l -ene-4- yne-3-ol. (ii) reacting the resulting 6,6-dimethyl-hept-l-ene-4-yne-3-ol with a mixture of phosphorous oxychloride and hydrochloric acid in methanol. (iii) extracting the reaction mass with aliphatic/aromatic solvent.0 (iv) removing the solvent under vacuum to give a residue. (v) reacting the residue obtained with N-(l-naphtylmethyl)methyl amine in the presence of a base to give Terbinafine. 4yϊ) Adding hydrochloric acid and extraction of the Terbinafine Hcl formed with a chlorinated solvent and 5 (vii) Recovering chlorinated solvent under vacuum and addition of ethylacetate to separate Temiriafiαeiiydrochloride which is filtered and dried.

2. An improved process as claimed of claim 1 wherein the base used in step ( v ) is selected from inorganic or organic.0

3. An improved process as claimed in claim 2 wherein the base used in is

fxαm sodium hydroxide, potassium hydroxide or trimethyl amine, diethylamine.

4. An improved process as claimed in claim 3, wherem the Terbinafine HCl formed iη s^e5 (vi) is extracted using

methylene chloήde, ethyUjne dichloride, or chloroform.

5. Ar^ improved ro ess_^ as clamed in clairη wherein, tiia chlorinated solvent is recovered

and.

HCl is isolated in ethyl- acejatø with of purity, >9P.9%, ajid yield of >$!,%.