PROCESS FOR PREPARING TRI-ARYL-ALKYLALKENES
FTELD OF THE INVENTION
The present invention relates to a process for preparing tri-arylalkylalkenes. Specifically, this invention relates to a process which utilizes a syn-elimination step allowing for the stereospecific synthesis of such compounds. Novel intermediates are also described.
BACKGROUND OF THE INVENTION A number of triarylalkylalkenes are known in the art as useful pharmaceutical agents. Examples of these include tamoxifen, droloxifene, panomifene, toremifene and idoxifene.
Preparation of these is compounds are described in the prior art; see U.S. Patents
4,536,516, 5,047,431; 4,806,685; 4,696,949 and 4,839,155. Preparation usually involves a dehydration final step to produce the alkene moiety usually under acid conditions. See also
J.Chem. Soc. Perkin Trans. 1,1011 (1987). This results in a mixture of stereoisomers which requires a separation step to obtain the desired compound.
For example, U.S. 4,839,155 describes a process for the synthesis of tri-arylalkyl alkenes including idoxifene. Specifically, U.S. 4,839,155 describes a process for the preparation of compounds having the formula:
wherein X represents 3- or 4- iodo or bromo and the R* and R^ symbols, which may be the same or different, represent C 1.3 alkyl, especially methyl or ethyl groups or R* represents a hydrogen atom and R^ a Cj_3 alkyl group or Rl and R^ together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, typically having 5 or 6
ring atoms, especially a pyrrolidino, piperidino, 4-methylpiperidino or morpholino group, and their pharmaceutically acceptable acid addition salts.
The prior art process comprises reacting l-[4-(2-chloroethoxy)phenyl]-2-phenyl-l- butanone with an organometallic reagent derived from 1,3- or 1,4-diiodo- or - dibromobenzene and capable of addition to a ketone group, in a substantially anhydrous organic solvent, to form a tertiary alcohol, dehydrating the tertiary alcohol to eliminate a molecule of water and thereby form l-[4-(2-chloroethoxy)phenyl]-l-(3- or 4-iodophenyl or -bromophenyl)-2-phenyl-l-butene as an isomeric mixture, separating the E isomer and reacting the E isomer with an amine of formula NR1R where R* and R^ are as defined above.
The prior art also describes a process for the preparation of the 3- and 4-iodo and - bromo tamoxifen derivatives which comprises reacting a ketone having the formula
R! and R^ being defined as above, in one step with an halophenylorganometallic reagent as defined above, in a substantially anhydrous organic solvent, to form a tertiary alcohol, dehydrating the tertiary alcohol to eliminate a molecule of water and thereby form l-[4-(2- NRlR^-substituted ethoxy)phenyl]-l-(3- or 4-iodophenyl or 4-bromophenyl)-2-phenyl-l- butene as an isomeric mixture, and separating the E isomer.
We have now discovered an improved process to prepare these triarylalkylalkenes. The syn-elimination process of this invention allows for the preparation of the desired isomer in less steps and in higher purity. Several novel intermediates are also part of the invention.
DESCRIPTION OF THE INVENTION
The present invention in its broadest aspect can be represented as follows:
wherein Ar*, Ar^ and Ar can be the same or different aromatic groups, R^ is alkyl and -
COR2 is an acyl derivative.
As used herein, alkyl means an alkyl group of 1-4 carbon atoms, branched or unbranched. Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t- butyl. The alkyl groups may be substituted with one or more halogen atoms such as fluorine and chlorine. Preferred alkyls are ethyl, trifluromethyl and 2-chloroethyl.
The acyl derivative -COR2 is an ester moiety derived from reagents listed but not restricted to, those in Table 1. The preferred acyl group is pivaloyl.
Also as used herein, the aromatic groups are unsubstituted or substituted phenyl as defined in US Patents 4,536,516, 5,047,431; 4,806,685; 4,696,949, 4,839,155 and 4,839,155 and are incorporated by reference. The preferred aromatic group is phenyl or alkoxy or halo substituted phenyl. The alkoxy substituent on a phenyl group can be further substituted with a nitrogen containing moiety such as dimethylamino, hydroxyethylamino and N-pyrrolidinyl. Novel intermediates include the generic ketones and esters noted:
wherein Ar , Ar Ar^, R* and R^ are as have been defined above.
The preferred process is depicted in the following scheme to form the compounds noted below:
The particularly preferred process is depicted in the following flow diagram.
The entire novel syn-elimination process for the preparation of idoxifene can be depicted as follows in Scheme 1.
Scheme 1
The procedure for the preparation of Compound II which is a novel intermediate is prepared by reacting the dianion of 2-phenylbutyric acid, prepared by reacting the acid with two equivalents of a strong base such as lithium diisopropylamine (LDA), with ethyl 4- iodobenzoate. The preferred mode is addition of the dianion to a solution of the ester. This mode of addition gives highly reproducible results particularly upon scale up and is tolerable to a wider range of temperatures, such that the whole procedure can be carried out at room temperature.
The bromide III is a commercially available compound. It can also be prepared by reaction of 4-bromophenol with 2-chloroethylpyrrolindine hydrochloride in the presence of a base. It can be converted to a Grignard reagent by standard procedures known by those skilled in the art. A procedure using trimethylsilyl chloride to initiate the reaction has been found advantageous. It is also advantageous to prepare the Grignard reagent using THF as the solvent. Compound II as a solution in 1,2,4-trimethylbenzene is added to the Grignard reagent.. It was found advantageous not to isolate Compound IV but to generate it in a solution of 1,2,4-trimethylbenzene, since this is the solvent of choice for the final elimination step. Alternatively, the Grignard reagent could be generated from Compound III by reaction with butyllithium followed by reaction with magnesium bromide. The Grignard reaction is quenched into aqueous sodium citrate solution or alternatively aqueous ammonium chloride or sodium chloride can be substituted. Residual water is removed by distillation to prevent interference with the next step.
The tertiary alkoxide is generated by reaction of Compound IV with potassium hexamethyldisilazide (KHMDS) or similar base. It has been found to be advantageous to use an excess of base to ensure complete formation of the alkoxide. The alkoxide is then acylated with trimethylacetyl chloride (pivaloyl chloride) which is also used in excess. Sodium and lithium bases, such as sodium hexamethyldisilazane, lithium hexamethyldisilazane and lithium diisopropylamide, may also be used, however potassium salts of strong bases are preferred. A wide number of acid chlorides are useful in this reaction and examples are set forth in Table 1 along with representative results for reactions in refluxing xylene without added base. Pivaloyl chloride is a preferred reagent. Alternative acylating reagents to the acid chloride could be employed such as the anhydride.
Compound V, which is a novel intermediate, can be isolated and purified by chromatography. A preferred procedure is to use the solution of 1,2,4-trimethylbenzene directly in the final stage syn-elimination reaction.
To achieve the syn-elimination, the solution of Compound V in 1 ,2,4-trimethylbenzene is heated to reflux. To sustain the high E/Z selectivity of the syn-elimination it is preferable to remove the pivalic acid generated during the course of the reaction by use of a scavenger and thereby lower the competing El elimination reaction. Useful scavengers include silylating agents and bases such as sodium carbonate and amines. Table 2 shows the results when pure Compound V is heated to reflux for 3 hours in 1,2,3-trimethylbenzene in the presence of various bases or silylating agents. It has been found that hexamethyldisilazane
- 1 ■
(HMDS) is the reagent of choice.
TABLE 2
Reaction temperature effects the length of reaction time for the elimination to go to completion. Reaction temperature also effects the E/Z selectively of the elimination. 1,2,4- Trimethylbenzene (b.p. 168°C) is preferred because it gave complete reaction within a reasonable time period (8 - 10 hours) and a high E/Z ratio. Other solvents can be used, specifically, nonane, decane, cumene, mesitylene, anisole, diglyme, butyl butyrate, 1,2- dichlorobenzene, hexanol have been used with sodium carbonate. Table 3 lists results of the elimination reaction on Compound V in various solvents using 10 mole equivalents sodium carbonate as the scavenger. In general more polar solvents give lower E/Z ratios.
TABLE 3
Compound VI is isolated, after aqueous work-up, by concentration and dilution with methanol to bring about crystallization. Equally the product could be isolated by evaporation to dryness and recrystallization of the residue from methanol or ethanol or iso- propanol. Salts and pharmaceutical formulations of Compound VI are prepared as taught in the prior art.
It will be clear to one skilled in the art that the above discussion regarding E/Z ratios should be read to mean Z/E ratios for those compounds where the desired triarylalkylene has the Z isomer notation. In addition, one skilled in the art will recognize that variation of the solvent, scavenger or acyl group may give varied results from compound to compound but high yields of the desired isomer can be obtained using the disclosed methods to choose conditions that favor the syn elimination over the E\ elimination.
Example 1A 1 -(4-iodophenyl)-2-phenyl- 1 -butanone
A solution of 2-phenylbutyric acid (1.25 mole equivalents) in dry THF (2 volumes) was added dropwise with stirring to 2.0 M lithium diisopropylamide in heptane/ethylbenzene/THF (2.45 mole equivalents ; 4 volumes) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours and then slowly added with stirring to a solution of ethyl 4-iodobenzoate (1.0 equivalents) in toluene (3.5 volumes) at room temperature. The reaction was stirred at room temperature for 0.5 hours and then slowly added with stirring to 5M hydrochloric acid (4.5 volumes) at room temperature. The organic phase was separated and washed with 1.2M aqueous sodium carbonate (3.5 volumes) and water (3.5 volumes) and then concentrated to 1.5 volumes by distillation under reduced pressure. The hot solution was diluted with iso- propanol (5 volumes). The mixture was cooled to 0°C and the product collected by filtration and washed with cold iso-propanol (2 volumes) to give the title compound as a white crystalline solid, m.p. 88-92°C
Example IB +/-Vl -[2-[4-[πS.2RVl-f4-iodophenyn-2-phenyl-1- hydroxybutyl]phenoxy]ethyl]pyrrolidine
Magnesium (1.35 mole equivalents) in dry THF (2.5 volumes) was treated with RedAl(TM) (1 - 4 mole %) under nitrogen. RedAl(TM) js bis(2-methoxyethoxy)aluminum sodium hydride in toluene, (MeOCH2CH20)2AlNaH , and is used to initiate the Grignard reaction. The reaction mixture was heated to 64°C and a 10% portion of a solution of l-[2-(4- bromophenoxy)ethyl]pyrrolidine (1.3 mole equivalents) in dry THF (2.5 volumes) is added. The reaction mixture was stirred at 64°C under nitrogen until initiation occurred. The remainder of the l-[2-(4-bromophenoxy)ethyl]pyrrolidine solution is then added dropwise with stirring maintaining reflux. The reaction mixture was refluxed for a further 0.5 hours and then cooled to room temperature. Alternate Procedure: Magnesium (1.35 mole equivalents) in dry THE (2.5 volumes) was treated with
trimethylsilyl chloride (1 - 4 mole %) under nitrogen. The reaction mixture was stirred at room temperature and a 10% portion of a solution of l-[2-(4- bromophenoxy)ethyl]pyrrolidine (1.3 mole equivalents) in dry THF (2.5 volumes) was added. The reaction mixture was stirred at 25-28°C under nitrogen until initiation occurred at which point the temperature rose to about 50°C. The remainder of the l-[2-(4- bromophenoxy)ethyl]pyrrolidine solution was then added dropwise with stirring and maintaining the temperature at 50 C. The reaction mixture was stirred at 50°C for a further 0.5 to 1 hour and then cooled to room temperature.
A solution of the title compound of Example 1 A (1.0 mole equivalent) in 1,2,4- trimethylbenzene (6 volumes) was added dropwise with stirring at room temperature to the Grignard solution prepared by either procedure above. The reaction mixture was stirred at room temperature for 0.5 hours and then slowly added to 0.75M aqueous sodium citrate (7.5 volumes) with gentle stirring. The organic phase was separated and washed with water (2 x 5 volumes). The THF and residual water was removed by distillation under reduced pressure leaving the title compound as a solution in 1 ,2,4-trimethylbenzene. This solution is used in the next stage without further purification.
Example 1C (+/-)- 1 -[2-[4-[( 1 S.2RV 1 -(4-iodophenyl V2-pheny1- 1 - trimethylacetoxybutyl]phenoxy]ethyl]pyrrolidine
The solution of the title compound of Example IB in 1,2,4-trimethylbenzene was treated with 16.6% w/w potassium hexamethyldisilazane in 1,2,4-trimethylbenzene (1.3 mole equivalents) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour and then treated with a solution of trimethylacetyl chloride (1.3 mole equivalents) in 1,2,4-trimethylbenzene (1 volume). The reaction mixture was stirred at room temperature for 0.5 hours and then washed with water (3 x 5 volumes). The organic phase was separated and the residual water removed by distillation under reduced pressure giving the title compound as a solution in 1,2,4-trimethylbenzene. This solution is used in the next stage without further purification. The title compound was isolated and identified by its nmr spectrum: 1H NMR (CDC13, 400MHZ, 300°K) δ 7.63(d, 2H), 7.2-7.1 (m, 5H), 6.90 (d, 2H) 6.80 (4.H), 4.42 (d, 1H), 4.13 (t, 2H), 2.92 (t, 2H), 2.64 (m, 4H), 1.96
(m, 1H), 1.82 (m, 4H), 1.26 (m, 1H), 0.88 (s, 9H), 0.72 (t,3H).
Example ID EVl-[2-[4-[l- 4-iodophenyl)-2-phenyl-l-butenyl]phenoxy]ethyl]pyrrolidine ("idoxifene^
The solution of the title compound of Example 1C in 1 ,2,4-trimethylbenzene was treated with hexamethyldisilazane (0.75 mole equivalents) and heated to reflux under a nitrogen atmosphere for 10 hours, at which point the syn-elimination is complete with an E/Z selectivity of 95:5. The reaction mixture is cooled to room temperature and washed with IM aqueous sodium carbonate (6 volumes) and water (2 x 5 volumes). The organic phase was separated and concentrated to less than 2 volumes. The hot solution was diluted while stirring with methanol (10 volumes). The reaction mixture was cooled to 0°C and the title compound collected by filtration and washed with cold methanol (2 volumes). Recrystallization from ethanol gives the product as a white crystalline solid in yields of 55- 69% based on the 1-butanone of Example 1A.
Example 2
Tamoxifen 1,2-Diphenylbutanone is reacted with a Grignard reagent prepared from (2- dimethylaminoethoxy)bromo benzene. The tertiary alcohol is reacted with a base followed by trimethylacetyl chloride to give the pivaloyl ester. The ester is refluxed in 1,2,4- trimethylbenzene with HMDS to yield the title compound.
Example 3 Droloxifene l-(3-t-Butyldimethylsilyloxyphenyl)-2-phenylbutanone is reacted with 4-(2- dimethlyaminoethoxy)benzene magnesium bromide to give the tertiary alcohol which is converted to the pivaloyl ester by the procedure of Example 1C. The ester is heated in 1,2,4,-trimethylbenzene at reflux with HMDS followed by removal of the silyl protecting group to give the title compound.
Example 4 Toremifene l,2-Diphenyl-4-chlorobutanone is reacted with 4-(2-dimethylaminoethoxy)benzene magnesium bromide to give the resulting tertiary alcohol. The alcohol is esterified with trimethylacetyl chloride and the ester is refluxed with HMDS in 1 ,2,4-trimethylbenzene to give the title compound.
Example 5 Panomifene
3,3,3-Trifluoro-l,2-diphenylpropanone is reacted with the Grignard reagent from 4-[2-(2- hydroxyethylamino)ethoxy]bromobenzene in which the hydroxy and amino groups are protected with a standard protecting group. The resulting tertiary alcohol is estified with trimethylacetyl chloride. Refluxing the ester in 1,2,4-trimethylbenzene with HMDS followed by removal of the protecting groups yields the title compound.