|Title of Invention||
A PROCESS FOR PREPARING AN AROMATIC CARBONYL COMPOUND AND AN ALPHA - ALPHA- DIBROMO -ALPHA- CHLORO ACETOPHENONE COMPOUND
|Abstract||This disclosure relates to the use of $g(a),$g(a)-dibromo-$g(a)-chloroacetophenone compounds as intermediates for the preparation of aromatic carbonyl compounds, especially aromatic amides. The compound 2,5-bis(2,2,2-trifluoroethoxy)-$g(a),$g(a)-dibromo-$g(a)-chloro-acetophenone is especially useful as an intermediate for the preparation of flecainide, a known pharmaceutical.|
α.α-DIBROMO-α-CHLORO-ACETOPHENONES AS SYNTHONS
a.a-Dibromo-a-chloro acetophenone compounds are reacted with nucleophiles to yield aromatic carbonyl compounds. In an important aspect, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide is prepared by reacting 2,5-bis(2I2l2-trifluoroethoxy)-a,a-dibromo-a-chloro acetophenone with 2-(2-aminomethyl)pyridine and reducing the piperidine ring.
2l5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyI)-benzamide (III) is a known medicament useful for the treatment of arrhythmia and is described in U.S. Patent No. 3,900,481. It is commercially available as its acetate salt. Methods for its synthesis are described, for example, in U.S. Patent Nos. 4,642,384 and 4,617,396.
The synthetic method described in U.S. Patent No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-αIα-dichloroacetophenone as an intermediate by chlorinating the a-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60°C. The a,a-dichloroaceto-phenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100°C to yield the a,a,a-trichloroacetophenone. The α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N"(2-piperidylmethyl)-benzamide.
The inventive process is based on the discovery that the a,a-dibromo-a-chloroacetophenone is easily prepared in high yield and purity under mild conditions, and that it is a superior leaving group in nucleophilic substitution reactions.
In one aspect this invention relates to a process for preparing the anti-arrhythmic agent, 2l5-bis(2,2l,2-trifIuoroethoxy)-N-(2-piperidylmethyl)-benzamide (III), commonly known as flecainide, and pharmaceutically acceptable salts thereof, in particular the acetate salt.
The synthetic route comprises the reaction of 2,5-bis(2,2,2-trifluoroethoxy)-a,a-dibromo-a-chloro acetophenone (I) with 2-(aminomethyl)pyridine to form the corresponding benzamide (II). The pyridyl ring of the benzamide (II) is then reduced to the piperidinyl moiety yielding the desired compound, flecainide acetate (III). The reaction scheme with preferred reagents is set forth below:
Since the bulky dibromochloromethyl group is an excellent leaving group, (I) undergoes a facile amidization reaction with 2-aminomethylpyridine under mild conditions, such as at room temperature. It is preferred to carry out the reaction in an inert, non-polar solvent, such as toluene, hexane and the like, preferably a mixture of toluene and hexane.
The reduction of pyridine rings to piperidine rings is well known and can be effected many means, such as hydrogenation, or reduction with a metal hydride, a metal or dithionite. Hydrogenation is carried out by contacting a solution of the benzamide (II) with hydrogen in the presence of a hydrogenation catalyst, such as Pt/C, Pt, Pt/Pt02 Pd/C, Rh/C, or Raney nickel. However, since it is unnecessary to protect any of the other functional groups in the molecule when the reduction is carried out by hydrogenation with a platinum-carbon catalyst, and since yields and purity are excellent, hydrogenation with a platinum-carbon catalyst is preferred.
Alternatively, for the preparation of flecainide, 2,5-bis(2,2,2-trifluoroethoxy)-a,a-dibromo-a-chloro acetophenone (I) can be reacted directly with 2-aminomethylpiperidine, avoiding the reduction step. However, the formation of impurities makes the two-step synthetic scheme described above preferable.
This invention further relates to the synthon 2,5-bis(2I2,2-trifluoroethoxy)-a,a-dibromo-a-chloro acetophenone (I). The bulky dibromochloromethyl group is an excellent leaving group for nucleophilic substitution reactions.
2>5-bis(2,2,2-trifluoroethoxy)-a,a-dibromo-a-chloro acetophenone (I) is preferably prepared from 2,5-bis(2,2,2-trifluoroethoxy)-a-chloro-acetophenone by reaction with bromine, preferably under neutral or acidic conditions, such as in glacial acetic acid in the presence of sodium acetate. Alternatively, other bromination methods, such as reaction with an N-bromoamide like N-bromosuccinimide, are also useful.
Example 1 1,4-B1S(2,2,2-TR1FLU0R0ETHQXY)-BENZENE
30.0 g (0.75 mole, 60% dispersion in oil) of anhydrous sodium hydride is added to a three-necked round bottom flask (500 mL) fitted with a condenser a with CaCI2 guard ube, a nitrogen inlet and a dropping funnel. 160 ml of dry dimethylformamide is added to nake slurry. The slurry is cooled in ice water and 2,2,2-trifluoroethanol (75 mL, 1.03 mole) s added drop wise resulting in an exothermic reaction. The temperature inside the flask is maintained below 30°C. During the addition of 2,2,2-trifluoroethanol, the mixture first becomes yellow in color and then becomes a brown clear solution. After the addition of the 2,2,2-trifluoroethanol is complete, the reaction mixture is stirred at room temperature for 30 minutes under a nitrogen blanket. 30.0 g (0.13 mole) of 1,4-dibromobenzene and 3.75 g of cupric bromide are then added. The resulting mixture is heated to 100°C with vigorous stirring for 2.5 hours. The reaction mixture is then cooled to room temperature and quenched with ice-water (1500 mL). The aqueous phase is acidified with about 50-55 ml of concentrated HCI. The resulting solid is filtered with vacuum and washed with copious amount of water. The violet-colored solid is dried overnight under vacuum in a desiccator over P205. The dried solid is dissolved in diethyl ether and filtered. The filtrate is evaporated resulting in an off-white solid (34.5 g, yield 99%), which is crystallized in n-hexane to yield needle-shaped crystals of 1,4-bis(2,2,2-trifluoroethoxy)-benzene. m.p. 74-77°C MS: M+ 274 (EI-MS) 1H NMR (CDCI3): 54.32 (4H,q,2,5-OCH2-CF3), 8 6.91 (4H,s, 1,3,4,6-H)
Example 2 2.5-BlSf2.2.2-TRIFLUOROETHOXYVa-CHLOROACETOPHENONE
A two-necked round bottom flask (250 mL) is fitted with a nitrogen inlet and a dropping funnel and 6.0 g (0.045 mole) of anhydrous aluminum chloride and 50.0 mL of dry methylchloride are added. A solution of 10.0 g (0.0365mole) of 1,4-bis(2,2,2-trifluoroethoxy)benzene dissolved in dichloromethane (10 mL) is added drop wise at room temperature with stirring followed by 4.0 mL (0.05 mole) of 2-chloroacetylchloride . The color of the solution slowly changes to red-brown. The mixture is stirred at room temperature for 2.5 hours. The red-brown colored solution is poured into a mixture of ice
The compound prepared according to Example 20 is converted to flecainide by (1) reaction with ethylchloroformate to form the N-carboethoxypiperidinyl derivative, for examplet by a procedure analogous to that described in U.S. Patent No. 4,282,233, followed by (2) decarbalkoxylation by known methods, for example, by a procedure analogous to that described in U.S. Patent No. 4,659,716.
Examples 22 and 23
0.322 g (0.016 mole) of sodium metal is placed in a 250 ml three necked round bottom flask fitted with a condenser and a dropping funnel. 50 ml of dry ethanol are added with cooling. After the addition is complete, the mixture is warmed to complete the formation of sodium ethoxide. The sodium ethoxide solution is added to 1.32 grams (0.015 mole) of dry ethyl acetate in Example 22 (or 1.62 g (0.015 mole) of benzyl alcohol in Example 23) and brought to room temperature. The mixture is then heated to 50-55°C
for about one hour. The mixture is then cooled in an ice bath, and 0.016 mole of the a,a-dibromo-a-chloro acetophenone compound dissolved in toluene is added slowly. After the addition is complete, the mixture is brought to room temperature and stirred for 2 hours. The solvent is evaporated under vacuum and the residue dissolved in water, acidified and extracted with methylene chloride. The combined methylene chloride fractions are washed with saturated brine and dried over sodium sulfate. Finally, the solvent is removed to yield the product.
A compound of claim 14 wherein at least one of R1 and R2 is substituted or unsubstituted C1-C4-alkyl; substituted or unsubstituted C3-C7-cycloalkyl; substituted or unsubstituted C1-C4-alkoxy; or substituted or unsubstituted -S-C1C4-alkyl.
17. A compound of claim 14 wherein at least one of R1 and R2 is substituted or unsubstituted C1-C4-alkoxy.
18. A compound of claim 14 wherein R^ is in the 4-position when R2 is hydrogen, or R^ is in the 2-position and R2 is in the 5-position when R2 is other than hydrogen.
19. A process for preparing an aromatic carbonyl compound substantially as herein described and exemplified.
|Indian Patent Application Number||22/CHENP/2003|
|PG Journal Number||26/2007|
|Date of Filing||06-Jan-2003|
|Name of Patentee||M/S. GENEVA PHARMACEUTICALS, INC.|
|Applicant Address||2655 West Midway Boulevard Broomfield, CO 80038|
|PCT International Classification Number||C07C231/10|
|PCT International Application Number||PCT/US01/21623|
|PCT International Filing date||2001-07-10|