(2E)-N-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide (1)
(S)-2′[2-1-(methyl-2-piperidyl) ethyl] cinnamanilide
(2E)-Λ/-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2- propenamide
CAS 951155-17-2
C23H28 N2O, 348.48
It was reported that the (S)-enantiomer of 2′-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide (MSA100, 1) is an active 5-HT (5-hydroxytryptamine or serotonin) receptor antagonist; however, its (R)-isomer is totally or substantially devoid of the same activity.(1)
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1.(a) Amer, M. S., U.S. Patent 5,780, 487, 1998.(b) Prashad, M.; Liu, Y.; Hu, B.; Girgis, M. J.; Schaefer, F., WO2007/111705, 2007.(c) Prashad, M.; Liu, Y.; Hu, B.; Girgis, M. J.; Schaefer, F., WO2007/111706, 2007.
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http://www.google.com/patents/WO2007111706A2?cl=en
Example 4:
Synthesis of (2E)-/V-[2-[2-[(2S)~1 -Methyl-2-piperidinyl]ethyI]phenyl]-3-phenyl-2- propenamide
(a) Free Base Generation:
A 250-mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, heating cooling bath, and addition funnel, is charged with 6.28 g (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (1R,3S)-(+)-camphoric acid salt (1 :1) and 60 mL of isopropyl acetate. Stir the mixture at 20-25 0C under nitrogen and add a solution of 1.60 g of sodium hydroxide in 20 mL of water over a period of 5 min while maintaining an internal temperature at 20-25 0C. Stir the suspension efficiently until all the solid dissolves (5 min). Separate the organic layer and save. Extract the aqueous layer with 20 mL of isopropyl acetate. Combine the organic layers and wash it with 20 mL of water. Separate the organic layer and concentrate it under vacuum (20-100 mbar) at an internal temperature at 20-40 0C (external temperature 30-60 0C) to obtain ~65 mL of a solution of (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (containing 3.28 g of free base) in isopropyl acetate. Save this solution for the next step and store it under nitrogen.
(b) Reaction:
A 250-mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet, heating mantle, condenser, and addition funnel is charged with -65 mL of a solution of (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (containing 3.28 g of free base) in isopropyl acetate and 6.22 g of potassium carbonate. Stir the reaction mixture under nitrogen at an internal temperature at 23 ± 3 0C to afford a suspension. Add 3.75 g of cinnamoyl chloride over a period of 5 min while maintaining an internal temperature at 23 ± 3 0C to obtain a slurry. Heat the reaction mixture to an internal temperature at 85 ± 5 0C (external temperature 90-100 0C) over a period of 30-60 min. Stir the reaction mixture at this temperature for an additional 2 h. Cool the reaction mixture to 23 ± 3 0C over a period of 1 h. Add 50 mL of water. Stir the reaction mixture at 23 ± 3 0C for 30-60 min to obtain a bi-phasic solution. Separate the organic layer. Add 80 mL of 0.5 N HCI solution over a period of 10 min while maintaining an internal temperature at 23 ± 3 0C to afford a bi-phasic solution. Separate the aqueous layer. Add 60 mL of isopropyl acetate. Stir the reaction mixture and add a solution of 2.00 g of sodium hydroxide in 25 mL of water over a period of 10 min while maintaining an internal temperature at 23 ± 3 0C to afford a bi- phasic solution. Separate the organic layer and save. Extract the aqueous layer with 60 mL of isopropyl acetate. Combine the organic layers and wash it with 40 mL of water. Separate the organic layer and concentrate it under vacuum (20-100 mbar) at an internal temperature at 20-40 0C (external temperature 30-60 0C) to obtain 22mL (19.3 g) of a solution of (iii) in isopropyl acetate. Stir and heat the reaction mixture to an internal temperature at 85 ± 5 0C (external temperature 90-100 0C) over a period of 30-60 min. Add 96 mL of hepatane over a period of 10 min while maintaining an internal temperature at 85 ± 5 0C. Stir and Cool the reaction mixture to 23 ± 3 0C over a period of 1 h. Stir the resulting slurry at 23 ± 3 0C for an additional 2 h. Collect the solid by filtration over a polypropylene filter paper in a Buchner funnel with suction. Wash the solid with a total of 28 mL of a mixture of isopropyl acetate and heptane (1/6) in two equal portions of 14 mL each. Dry the solid at 45-50 0C under vacuum (13-40 mbar) with nitrogen bleeding to obtain a constant weight (LOD < 1%, 4 h) of 4.06 g of (2£)-A/-[2-[2-[(2S)-1-methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide as an off white solid.
Theoretical Yield: 5.23 g
Yield: 77.6%
Purity: 99.8% (HPLC area %).
Enantiomeric purity: (R)-(iii) was not detected by Chiral HPLC. Example 5:
Alternative synthesis of (2£)-/V-[2-[2-[(2S)-1-MethyI-2-piperidinyl]ethyl]phenyI]-3- phenyl-2-propenamide
(a) Free base generation:
In a 500 ml round bottomed flask equipped with a mechanical stirrer the resolved camphoric acid salt (IV) (20 g) in isopropyl acetate (120 g) is added at an internal temperature of 20 to 25 0C (external temperature 20 0C). Then, at an internal temperature of 25 to 30 0C (external temperature 20 0C) a solution of sodium hydroxide (38.24 g) in water (60 g) is added to the reaction mixture over a period of 5 minutes. The reaction mixture (suspension) is then stirred for a further 30 minutes. The resulting orange emulsion is then allowed to separate into a two-phase mixture and the water phase is removed. The organic phase is then subjected to a rotary evaporator and the isopropyl acetate is distilled at an internal temperature of 60 0C and under reduced pressure (250 mbar). Approximately 90 g of isopropyl acetate is distilled. Prior to distilling, the organic phase is a clear, bright orange colour and of a volume of approximately 160 ml ( 13Og),
(b) Reaction:
In a 1.5 I flask equipped with a mechanical stirrer and at an internal temperature of 35 0C (external temperature 38 0C) and under inert conditions (nitrogen) 2-butanone (160 g) and isopropyl acetate (20 g) is added to the reaction mixture of part (a). Then, at an internal temperature of 35 0C (external temperature of 38 0C) a solution of cinnamoyl chloride (8.9 g) in 2-butanone (20 g) is added drop wise. Then, the reaction mixture is treated with more 2- butanone (2 x 5 g). The resulting suspension is then stirred for 20 minutes at an internal temperature of 350C. The pH of the mixture is between 6 and 8.
(c) Resolution:
The suspension of step (b) is then cooled to an internal temperature of 25 0C (external temperature 20 0C) and at the same time a mixture of water (200 g) and isopropyl acetate (60 g) is added. The reaction mixture is then stirred for a further 15 minutes at an internal temperature of 25 0C (external temperature 20 0C). The resulting two-phase reaction mixture is then separated and the water phase removed. The resulting yellow upper layer is then treated with 2.5 mol/l hydrochloric acid (200 g). The resulting two-phase mixture is then separated and the water phase is transferred into a 750 ml flask equipped with a mechanical stirrer. The organic phase is then washed with 2.5 mol/l hydrochloric acid (200 g) and the resulting two-phase mixture is separated and the water phase is added to the first water phase. The combined water phases are then treated with acetic acid (300 g) and sodium hydroxide (150 g) is added. The reaction mixture is then stirred at an internal temperature of 25 to 30 0C (external temperature 20 0C) for 15 minutes. The resulting two-phase reaction mixture is then separated.
(d) Crystallization
The organic phase from the above reaction step (c) is reduced in volume on a rorary evaporator at an external temperature of 60 0C and at 250 mbar. Then, the reduced-volume reaction mixture is treated with isopropanol (60 g) and the resulting reaction mixture is reduced in volume on a rotary evaporator at an external temperature of 60 0C and under a vacuum of 150 mbar. Then, at an internal temperature of 50 to 55 0C (external temperature 60 0C) the reaction mixture is treated with water (20 g) and the resulting suspension is further treated with the product (iv) (10 mg) in isopropanol (0.01 g). The reaction mixture is then stirred for a further 15 minutes at an internal temperature of 50 to 55 0C (external temperature 60 0C). Then, further water is added over a period of 15 to 30 minutes and the reaction mixture is maintained at an internal temperature of 50 to 55 0C (external temperature 60 0C). Then, the resulting suspension is cooled to an internal temperature of 22 to 22 0C (external temperature 20 0C. Then, the suspension is stirred for a further 30 minutes at an internal temperature of 22 to 22 0C (external temperature 20 0C) and the resulting solid is collected by filtration and washed with a mixture of water and isopropyl acetate (2 x 20 g), where the water: isopropyl acetate ratio is of 5:1 g/g. The resulting solid may then be dried under a vacuum at a temperature of 55 0C.
Yield: 14.8 g (89.3% of theory). mp: 127.3 to 130.2 0C
Example 6: Recrystallisation of (2E)-Λ/-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2- propenamide
(a) In a 200 ml round bottomed flask equipped with a magnetic stirrer, containing the product (iv) (15 g) is added isopropanol (25 g) and heptane (heptane fraction from petroleum having a boiling point of 65 to 100 0C) (25 g) is added. Then, the reaction mixture is heated to an internal temperature of 75 0C (external temperature 95 0C) and refluxed for approximately 30 minutes, whilst stirring. Then, the reaction mixture is filtered over a glass fibre filter at an internal temperature of 70 to 75 0C (external temperature 85 0C) in to a 350 ml flask equipped with a magnetic stirrer. Then, a mixture of isopropanol (5 g) and heptane (5 g) is added and the reaction mixture is heated to an internal temperature of 70 0C (external temperature 95 0C). Then, further heptane is added drop wise to the reaction mixture at an internal temperature of 65 to 75 0C (external temperature 75 0C).
(b) Crystallization
The solution from step (a) is then cooled to an internal temperature of 40 0C (external temperature 40 0C) over a period of 15 minutes. The, at an internal temperature of 40 0C, the solution is treated with a suspension of the recrystallized product (v) (11 mg) in heptane is added and the reaction mixture is stirred for 30 minutes at an internal temperature of 40 0C (external temperature 40 to 45 0C). Then, the reaction mixture is treated with some further heptane (15 g) at an internal temperature of 40 0C. The resulting suspension is then cooled to an internal temperature of -10 0C (external temperature -10 to -15 0C) over a period of 30 minutes and then further stirred for a further hour. The reaction mixture is then filtered at an internal temperature of -10 0C (external temperature -10 to -15 0C) and the resulting solid may be washed in a mixture of isopropanol and heptane, where the isopropanohheptane ratio is 1 :1.5. The solid may be washed twice (2 x 11.25 g). The solid may then be dried in a vacuum at a temperature of 60 0C.
Yield: 17.8 g (89% of theory) mp: 127.4 to 132.0 0C.
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An efficient process was developed for the manufacture of MSA100, a serotonin receptor antagonist, via a five-step synthetic route furnishing a high quality of active pharmaceutical ingredient. Highlights of this synthesis include: (1) replacing carcinogenic methyl iodide with methyl p-toluenesulfonate as the methylating reagent; (2) a hydrogenation protocol with optimized temperature, pressure, and mass-transfer conditions that avoided one side product and reduced the other one effectively; (3) chemical resolution employing D-camphoric acid in a mixed-solvent system; (4) amidation under anhydrous conditions for controlling a Michael adduct impurity; and (5) plausible mechanisms for the formation of side products.
Example I PREPARATION AND CONFIRMATION OF S-MPEC
racemic-APEMEP-HI -5/1-
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1. 2 – nitrobenzaldehyde
2. 2 – picoline
3. 2 – (o-nitrostyryl) pyridine (NSP)
4. 2 – “(o-nitrostyryl)- 1 -methylpyridinium iodide 5. RS-2- (o-aminophenethyl)-l-methylpiperidine. HI
6. S-[2-(o-aminophenethyl)- 1 -methylpiperidine-dibenzoyl-L-tartrate] (S-APEMP. DBLT OR .L-DBT)
7. S-2′- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide (S-MPEC) 7a. Cinnamoyl chloride S-MPEC CHEMICAL PROCESS
(A) 2-(O-Nitrostyryl) – 1 -Methylpyridinium Iodide fNSMP-P
To a 50 L round bottomed flask was added 2-nitrobenzaldehyde (3,500 g. 23.2 moles), 2-picoline (3.2L., 32.8 moles) and acetic anhydride. The mixture was stirred efficiently under an inert atmosphere (nitrogen or another inert gas) and heated to reflux for 27 hrs. The mixture was cooled to under 100 C, for safe handling, and quenched in a suitable vessel equipped with external cooling and efficient stirring on 10.5 Kg. of ice. The pH was adjusted to 11 with 45% aqueous sodium hydroxide at a rate to keep the temperature below 50°C. After cooling to 20-30°C, the granular solid was collected by filtration, washed well with water. Yield 6572 g. of crude 2-(o-nitrostyryl) pyridine (NSP).
This solid was transferred to a 50L, round bottomed flask, dissolved in acetone (14L.) and iodomethane (2.94L., 47.7 moles) (quaternizing methylating agent) was added. (Other such (alkylating) agents may be used, generally having the formula CH3X, X being an anion such as sulfate, methyl sulfate, halide (Cl, Br, I), etc.). The mixture was heated to reflux under an inert atmosphere (nitrogen or another inert gas) for 18 hrs. After cooling to 20°C. the precipitate was collected by filtration and washed with acetone or a 1 :1 mixture of acetone:ethyl acetate (3×3.5L.). Drying to constant weight at 50-60°C. yielded 6,839 g. (80%) of NSMP.I. (B) RS- 2-(o-Aminophenethyl)-l-Methylpiperidine. Hvdroiodide
ΓRS-APEMP.HΠ
In a 5 gallon reactor, a solution of NSNP.I (935 g., 2.5 moles) in – 7 – methanol (14L.) was reduced in a hydrogen atmosphere (Psi. 55) in the presence of Pt/C (5 or 10%, 98g.). After removal of the catalyst and evaporation of the filtrate in the usual manner, the residue was dissolved in hot methanol (2.8L.). Ethyl acetate (2.8L) was added to the hot mixture to induce crystallization, yield 516.3 g. (59%) of RS-APEMP.HI.
(C) S-[2-(o-Aminophenethv0- 1 -Methylpiperidine Dibenzoyl-L-Tartrate] (S- APEMP.DBLT)
A solution of RS-APEMP.HI (516g., 1.5 mole) ethyl acetate (5.5g.) (or other low boiling water immiscible solvent such as benzene, toluene etc.) was extracted with 5% aqueous sodium hydroxide to liberate the free base (organic phase), washing the organic phase with water, drying over a suitable drying agent (such as anhydr. sodium sulfate, magnesium sulfate, potassium carbonate etc.) After separating the solvent from the drying agent the solution was evaporated in vacuo and the residual RS-APEMP free base was dissolved in methanol (l .O.L.) and a solution of dibenzoyl-L-tartaric acid (540 g., 1.5 moles) in methanol (2.3 L.) was added. The mixture was held overnight at room temperature. The crystalline precipitate was collected and recrystallized from methanol (3.4 L.), yield 246g. of S-APEMP.DBLT. (28.6%, wt; 57.2% of the S-APEMP). (O) S-2′-r2-π-Methyl-2-Piperidvnethyll Cinnamanilide f S-MPEC) A solution of S-APEMP.DBLT (287 g, 0.5 mole) in ethyl acetate
(3.2 L.) (or other low boiling water immiscible solvent) was extracted with 7.5% aqueous sodium bicarbonate (3.2 L.) to liberate the S-APEMP. After a water wash and drying over a suitable drying agent the solvent was removed in vacuo. The oily residue, S-APEMP, was dissolved in ethyl acetate (1.0 L.) and anhydrous potassium carbonate (412 g, 3.0 moles) (or other suitable acid acceptor such as triethyl amine, pyridine etc.) was added. Cinnamoyl chloride (143 g., 0.7 mole) in 700 ml. of ethyl acetate was added slowly. After the initial reaction, the mixture was refluxed for 14 hrs. After cooling to room temperature the mixture was extracted with water (1.7 L.) and dried over a suitable drying agent. After removing the drying agent the solvent was removed in vacuo and the residue was dissolved in hot ethyl acetate (280 ml.) and allowed to slowly cool to room temperature; filtration yielded S-MPEC, (136 g., 79% yield). Analysis: Calcd. For C, H, N : C, 79.27; H, 8.10;N, 8.04. Found: C, 79.27; H, 8.06; N, 8.07. HPLC(chiral)purity: 99.5%, [oc ]D25, -46° (c=0.01,EtOH); Melting point: 128°C.
TABLE 2 CERTIFICATE OF ANALYSIS Compound Name: (-)-2′-[2-(l-Methyl-2 piperidyl)ethyl]cinnamanilide(/-MPEC,S- MPEC
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synthesis of 2′[2-1-(methyl -2-piperidyl) ethyl] cinnamanilide (Y1), which is a compound of formula (Y) where Ra is hydrogen and R1 is methyl:
Processes for the preparation of compounds of formula (Y) are described in U.S. Pat. No. 3,931,195 which comprises the step of alkylating compounds of formula (i) (below) with an alkyl halide, such as methyl iodide for methylation. The same methylation step is described in EP0973741 for the synthesis of compound (Y1).
Thus, the processes described in the prior art involve the use of a highly toxic reagent (e.g. methyl iodide) and provides a yield of about 50%
Filed under: Preclinical drugs Tagged: MSA 100, preclinical
