CA2122584A1 - A process for the resolution of (+-)-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide - Google Patents
A process for the resolution of (+-)-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamideInfo
- Publication number
- CA2122584A1 CA2122584A1 CA002122584A CA2122584A CA2122584A1 CA 2122584 A1 CA2122584 A1 CA 2122584A1 CA 002122584 A CA002122584 A CA 002122584A CA 2122584 A CA2122584 A CA 2122584A CA 2122584 A1 CA2122584 A1 CA 2122584A1
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- methylethyl
- chlorophenyl
- piperidinebutanamide
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
Abstract
2122584 9313087 PCTABS00024 A process for the resolution of (+-)-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1_ -piperidinebutanamide having structure (I) into its (+) and (-) enantiomers using camphorsulfonic acid.
Description
WO g3/13087 2 1 2 2 5 8 ~ PCI`/US92/10020 _ 1 _ A PROCESS FOR lHE RESOLUTION OF (+-)-cL-¦2-[ACElYL(I-METHYLETHYL)AM1NO]ETHYL]-u-(2-CHLOROPHENYL)-I-PIPERIDINEB11TANAMIDE
(+)-c~-t2-~Acetyl(l-methylethyl)aminc~ethyl~ (2-chlorophenyl)-l-piperidinebutanamide which is a racemic mixture is useful by virtue of its ability to inhibit ventricular arrhythmia. A complete discussion of (+)~-t2-~acetyl(l-methylethyl)~mino~ethyl~ t2-chlorophenyl)-l-piperidinebutan~mide usefulness as an ~ntiarrhythmic agent is given in United States Patent :
4,639,524. Given its potential usefulness as a pharmacological agent, it beca~e desirable to develop a convenient and cost effective process for its resolution.
Background of the Invention Ingersoll, J. Am. Chem. Soc. ~47), 1168-1173 (1925) discusses a method for the resolution of externally compensated acids and bases by which both active forms are obtained completely pure. This method utilizes stereospecific c~mphorsulfonic acid.
In~ersoll, J. Am. Chem. Soc. (50), 2264-2267 (192R) discusses the resolution of inactive iso-diphenylhydroxy-ethyiamine with d and dl-camphor sulfonic acids.
W093/1 ~ 7 PCT/US92/10020 Summarv of the InYention The pre6ent invention providas a convenient and cost effective manufacturing process for the resolution of (+~ t2-[acetyl(l-methylethyl)amino~ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide into its two enantiomers - ~+]-~-t2-~acetyltl-methylethyl) amino]ethyl]-~-(2-chlorophenyl)-~-piperidinebutanamide which is represented by the foll~wing s~ructural formula O
¢~N~
Cl and [-]-~-C2-~acetyl(l-methylethyl) aminoethyl~ (2-chlorophenyl)-l--piperidinebutanamide . . .
which is represented by the following structural formula . .
WO93/1~7 2 ~ 2 2 ~ 8 4 PCr/US92/10020 Cl N
Both enantiomers sh~w electrophysiolo~ic e~fects in both the upper and lower parts of the heart. This electrophysiological activity would indicate that the enanti~mers would be useful a antiarrhyth~ic ag~nts.
The convenienc~ of the process is demonstrated by the synthetic route comprising only two step~. The cost effectiveness of the process is demonstrated by the final product being produced in high yield and high quality.
The process of this invention is illustrated by the following Scheme I.
, 2 12 2 5 $ 4 4 PCr/US92~10020 Scheme I
O~z~ ., WO 93J13087 2 1 2 2 5 ~ ~ PCr/US9i~/10020 Scheme I (cont. ) [~
!.-W093/13087 2 12 2 5 8 ~ PCT/US92/10020 In the practice of this invention which is illustrated in Scheme I, ~+~-~-t2-~acetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-1-piperidinebutanamide is mixed in an organic solvent and (lR)-(-)-10 camphorsulfonic acid is added to the solution. The solid [+~ 2-[acetyl(1-methylethyl)amino]ethyl~-~-(2-chlorophenyl)-1-piperidinebutanamide(-)camphorsulfonic salt is obtained by filtration. In a preferred embodiment of the invention the stereospecific camphorsulfonic acid is added to a mixture of acetone and ~+]-a-t2-~acetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-1-piperidinebutanamide and the resulting solution is stirred. Seeding of the solution with t+~ 2-tacetyl(l-methylethyl)amino~ethyl~-~-(2-chlorophenyl)-l-piperidinebutanamide(-)camphorsulfonic acid salt initiates the crystallization of t+}-~-t2-tacetyl(1-methylethyl)amino]ethyl~ (2-chlorophenyl)-1-piperidinebutanamide(-)camphorsulfonic salt. ~he solvent is removed by filtrating. The crystalline product is washed with acetone, pulled dry under N2 and dried in a vacuum oven at 50 C. While acetone is a preferred solvent, other solvents such as ethyl acetate and methylethyl ketone could be used in the practice of this invention.
The diastereomeric salt is converted to t+]-~-t2-tacetyl(l-methylethyl)amino~ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide by treatment with a base. In a preferred, embodiment of the invention the free b~se formation i~ conducted at room temperature for fifteen minutes. The diastereomeric ~alt is dissolved in water and methylene chloride. The reaction mixture is stirred and then treated with ammonium hydroxide. The organic layer i8 washed with water, dried and filtered.
Removal of the solvent gives ~+]-~-t2-tacetyl(l-methylethyl)amino] ethyl~-~-(2-chlorophenyl)-1-W093/1~87 ~ 1 2 2 ~ 8 4 PCT/US92/10020 piperidinebutanamide as a crystalline product. While ammonium hydroxide is a preferred base, other bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate could be used.
The filtrate from the preceding filtration step is - concentrated to give a solid which is treated with base as described above to provide a mixture of ~]~ 2-[acetyl(l-methylethyl)amino~ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide and ~ 2-[acetyl(l-methylethyl)aminoethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide. This mixture is enriched in the (-) enantiomer mixture. It is essential in the practice of this invention that the percentage of the (-) enantiomer in the enriched mixture not be below 70%
with 80% or above being preferred. This mixture is mixed with (+)-camphorsulfonic acid in acetone. After -seeding with ~ t2-[acetyltl-methylethyl) aminoethyl~ (2-chlorophenyl)-l-piperidinebutanamide (+)-camphorsulfonic acid salt and crystallization the E~ 2-tacetyl(~-methylethyl)aminoethyl~ (2-chlorophenyl)-l-piperidinebutanamide (+)-camphorsulfonic acid salt is isolated by filtration.
This salt is treated with base in the manner described above to provide ~-]~ 2-~acetyl(l-methylethyl)aminoethyl]-~-(2-chlorophenyl)~l-piperidinebutanamide.
The stereospecific camphorsulfonic acid, namely the (lR)-(-)-lO camphorsulfonic acid or (lS)-(+)-lO-camphorsulfonic acid is commercially available~
. .
The following examples are intended to further illustrate the present invention and not to limit the invention in spirit or scope. In the examples, all parts are parts by weight and temperature is in degreas Celsius unless otherwise expressly set forth.
WO93/1~87 2 1 2 2 ~ ~ l PCT/USg2/1~20 XaMPL~ (46521) Preparation of ~ +)-~-~2-tacetyl(1-methylethyl) amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide N
Cl Ste~ A (~) 730 g of t+~-~-t2-tacetyl~1-methylethyl)amino]
ethyl]-~-t2-chlorophenyl)-l-piperidinebutanam_de wa~ ~ixed with 5.5 mL of acetone in a flask equipped with a mechanical stirrer. To the stirred mixture was added 416 g of (lR)-(-)-lO-camphor ~ulfonic acid and an additional S00 ml of acetone. Addition caused th~
temperature of the solution to ri~e to 50~C. The stirred solution was now seeded with 100 mg of (+)-~-~2-[acetyl(l-methylethyl)amino]ethyl]-~-t2-chlorophenyl)-l-piperidinebutanamide (-)-cam p orsulfonic acid salt and stirring was continued overnight.
The resulting ~ine particle crystalline product was filtered, washed with acQtone, and pulled ~y under N2. The filtrate containing an enriched mixture Of t-]-~-~2-tacetyl(l-~ethylethyl)aminoethyl~-~-(2-chlorophenyl)-1-piperidinebutanamide(-)camphorsulphonic acid salt is used in Example 2.
WO93~13087 2 1 2 2 5 8 ~ PCT/US92/1~20 _ g _ Drying of the product in a vacuum o~en at 50C
overnight gave 437 g of the salt. The salt had the following elemental analysis:
Required for ~H50ClN306S: c, 60.03; H, 7.87; N, 6.56;
Cl, 5.54; S, 5.01 Found: C, 60.06; H, 7.93; N, 6.59; Cl, 5.28; S, 5.14 m~p. 191.5-193C.
Step B
The product of Step A (436 g) was dissolved in 1500 ml of water. To this solution was added 2000 ml of methylene chloride and 92 ml of 29.4% ammonium hydroxide solution. The solution was now stirred for 15 minutes. The organic layer was separated, washed (2x) with 1 L ~f water, dried over anhydrous K~C03 and filtered. Btripping of the solvent under vacuum yielded 294 g of th~ crude product. The crude product was dissolved in 2 L of refluxing ethyl acetate and filtered while hot. The filtrate was transferred to a flask equipped with a magnetic stirring bar and stirred. Seeding of the filtrates with t+]-~-[2-racetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide caused the product to crystallize as a thick slurry. Stirring was discontinued and the slurry was allowed to stand o~ernight. The slurry was broken up, filtered and washed with 200 ml of ethyl acetate. The product was pulled dry and then dried in a vacuum at 50C. Tbis procedure gave 239 g of the title product.
Concentration of the filtrates gave additional ~+]--r 2-ta~ètyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide for an overall yield of 70%.
s The title product had the following elemental analysis:
WO g3/13087 PC~/US92/10020 2122584 - lo-Required for C22H34ClN30~: C, 64.77; H, 8.40; N, 10.30;
Cl, 8.69 Found: C, 64.73; H, 8.58; N, 10.20; Cl, 8.76 Specific Rotation: t~r~D25S+4 . go (C=1 in CHCl3) .
2i2`2~8~
WO93/1~87 PCT/US9~/10020 EXAMPLE 2 (46562) Preparation of 2-[acetyltl-methylethyl) amino]ethyl]-~ t2-chlorophenyl)-l-piperidinebutanamide O
~_N~
Cl St~p ~
The filtrate from example l containing an enriched ~ample of [-]-~-t2-[acetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-1-piperidinebutanamide(-)-camphorsulphonic acid salt was concentrated to a solid weighing 613 g. The material was taken up in 1500 ml of water then made basic with ammonium hydroxide (100 ml). The mixture was extracted with two 700 ml portions of methylene chloride. The organic layers were drisd over K2C03 and filtered. The filtrate was concentrated to pro~ide 417 g of an enriched sample of ~ t2-[acetyl(1-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide. To this product in 2.0 L of acetone with stirring is added (+)-camphorsulfonic acid (207 g). The solution is seeded wi~h (-~-~-t2-tac~tyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl~-1-piperidinebutanamide(+)-camphorsulfonic acid and an additional 500 ml of acetone is added.
Stirring was continued overnig~t. The resulting fine W093/130~ PCT/US92/1~20 2122~8~ - 12 -particle crystalline product was filtered, washed with acetone, and pulled dry under N2. Drying of the product in a vacuum oven at 50C overnight gave 404 g of the salt.
m.p. 190-193C.
Step B
The product of Step A (404 g) was dissolved in 1200 ml of water. To this solution was added 1400 ml of methylene chloride ~nd 120 ml of 29.4% ammonium hydroxide solution. The solution was now stirred ~or 15 minutes. The organic layer was separated, washed (2x) with 1 L of water, dried over anhydrous K2Co3 and filtered. Stripping of the solvent under vacuum yielded 335 g of the crude proclct. The crude product was dissolved in 2 L of refluxing ethyl acetate and filtered hot. The filtrates were transferred to a flask equipped with a magnetic stirring bar and stirred. Seeding of the filtrates with [~ -t2-E acetyl~l-methylethyl)amino]ethyl]-~-~2-chlorophenyl)-l-piperidinebutanamide cau~ed the product to crystallize as a thick slurry. Stirring was diccontinued and the slurry was allowed to stand overnight~ The slurry was broken up, filtered and washed with 200 ml of ethyl acetate. The product was pulled dry and then dried in a vacuum over at 50C.
This procedure gave 255 g of the title product.
The title product had the following elemental analysis:
Required for C~H~ClN302: C, 64.77; ~, 8.40; N, 10.30;
Cl, 8.~9 Found: C, 64.7~; H, ~.58; N, 10.20; Cl, 8.76 Specific Rotation: ~]D~=-5-4 (C=l in CHCl3).
(+)-c~-t2-~Acetyl(l-methylethyl)aminc~ethyl~ (2-chlorophenyl)-l-piperidinebutanamide which is a racemic mixture is useful by virtue of its ability to inhibit ventricular arrhythmia. A complete discussion of (+)~-t2-~acetyl(l-methylethyl)~mino~ethyl~ t2-chlorophenyl)-l-piperidinebutan~mide usefulness as an ~ntiarrhythmic agent is given in United States Patent :
4,639,524. Given its potential usefulness as a pharmacological agent, it beca~e desirable to develop a convenient and cost effective process for its resolution.
Background of the Invention Ingersoll, J. Am. Chem. Soc. ~47), 1168-1173 (1925) discusses a method for the resolution of externally compensated acids and bases by which both active forms are obtained completely pure. This method utilizes stereospecific c~mphorsulfonic acid.
In~ersoll, J. Am. Chem. Soc. (50), 2264-2267 (192R) discusses the resolution of inactive iso-diphenylhydroxy-ethyiamine with d and dl-camphor sulfonic acids.
W093/1 ~ 7 PCT/US92/10020 Summarv of the InYention The pre6ent invention providas a convenient and cost effective manufacturing process for the resolution of (+~ t2-[acetyl(l-methylethyl)amino~ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide into its two enantiomers - ~+]-~-t2-~acetyltl-methylethyl) amino]ethyl]-~-(2-chlorophenyl)-~-piperidinebutanamide which is represented by the foll~wing s~ructural formula O
¢~N~
Cl and [-]-~-C2-~acetyl(l-methylethyl) aminoethyl~ (2-chlorophenyl)-l--piperidinebutanamide . . .
which is represented by the following structural formula . .
WO93/1~7 2 ~ 2 2 ~ 8 4 PCr/US92/10020 Cl N
Both enantiomers sh~w electrophysiolo~ic e~fects in both the upper and lower parts of the heart. This electrophysiological activity would indicate that the enanti~mers would be useful a antiarrhyth~ic ag~nts.
The convenienc~ of the process is demonstrated by the synthetic route comprising only two step~. The cost effectiveness of the process is demonstrated by the final product being produced in high yield and high quality.
The process of this invention is illustrated by the following Scheme I.
, 2 12 2 5 $ 4 4 PCr/US92~10020 Scheme I
O~z~ ., WO 93J13087 2 1 2 2 5 ~ ~ PCr/US9i~/10020 Scheme I (cont. ) [~
!.-W093/13087 2 12 2 5 8 ~ PCT/US92/10020 In the practice of this invention which is illustrated in Scheme I, ~+~-~-t2-~acetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-1-piperidinebutanamide is mixed in an organic solvent and (lR)-(-)-10 camphorsulfonic acid is added to the solution. The solid [+~ 2-[acetyl(1-methylethyl)amino]ethyl~-~-(2-chlorophenyl)-1-piperidinebutanamide(-)camphorsulfonic salt is obtained by filtration. In a preferred embodiment of the invention the stereospecific camphorsulfonic acid is added to a mixture of acetone and ~+]-a-t2-~acetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-1-piperidinebutanamide and the resulting solution is stirred. Seeding of the solution with t+~ 2-tacetyl(l-methylethyl)amino~ethyl~-~-(2-chlorophenyl)-l-piperidinebutanamide(-)camphorsulfonic acid salt initiates the crystallization of t+}-~-t2-tacetyl(1-methylethyl)amino]ethyl~ (2-chlorophenyl)-1-piperidinebutanamide(-)camphorsulfonic salt. ~he solvent is removed by filtrating. The crystalline product is washed with acetone, pulled dry under N2 and dried in a vacuum oven at 50 C. While acetone is a preferred solvent, other solvents such as ethyl acetate and methylethyl ketone could be used in the practice of this invention.
The diastereomeric salt is converted to t+]-~-t2-tacetyl(l-methylethyl)amino~ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide by treatment with a base. In a preferred, embodiment of the invention the free b~se formation i~ conducted at room temperature for fifteen minutes. The diastereomeric ~alt is dissolved in water and methylene chloride. The reaction mixture is stirred and then treated with ammonium hydroxide. The organic layer i8 washed with water, dried and filtered.
Removal of the solvent gives ~+]-~-t2-tacetyl(l-methylethyl)amino] ethyl~-~-(2-chlorophenyl)-1-W093/1~87 ~ 1 2 2 ~ 8 4 PCT/US92/10020 piperidinebutanamide as a crystalline product. While ammonium hydroxide is a preferred base, other bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate could be used.
The filtrate from the preceding filtration step is - concentrated to give a solid which is treated with base as described above to provide a mixture of ~]~ 2-[acetyl(l-methylethyl)amino~ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide and ~ 2-[acetyl(l-methylethyl)aminoethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide. This mixture is enriched in the (-) enantiomer mixture. It is essential in the practice of this invention that the percentage of the (-) enantiomer in the enriched mixture not be below 70%
with 80% or above being preferred. This mixture is mixed with (+)-camphorsulfonic acid in acetone. After -seeding with ~ t2-[acetyltl-methylethyl) aminoethyl~ (2-chlorophenyl)-l-piperidinebutanamide (+)-camphorsulfonic acid salt and crystallization the E~ 2-tacetyl(~-methylethyl)aminoethyl~ (2-chlorophenyl)-l-piperidinebutanamide (+)-camphorsulfonic acid salt is isolated by filtration.
This salt is treated with base in the manner described above to provide ~-]~ 2-~acetyl(l-methylethyl)aminoethyl]-~-(2-chlorophenyl)~l-piperidinebutanamide.
The stereospecific camphorsulfonic acid, namely the (lR)-(-)-lO camphorsulfonic acid or (lS)-(+)-lO-camphorsulfonic acid is commercially available~
. .
The following examples are intended to further illustrate the present invention and not to limit the invention in spirit or scope. In the examples, all parts are parts by weight and temperature is in degreas Celsius unless otherwise expressly set forth.
WO93/1~87 2 1 2 2 ~ ~ l PCT/USg2/1~20 XaMPL~ (46521) Preparation of ~ +)-~-~2-tacetyl(1-methylethyl) amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide N
Cl Ste~ A (~) 730 g of t+~-~-t2-tacetyl~1-methylethyl)amino]
ethyl]-~-t2-chlorophenyl)-l-piperidinebutanam_de wa~ ~ixed with 5.5 mL of acetone in a flask equipped with a mechanical stirrer. To the stirred mixture was added 416 g of (lR)-(-)-lO-camphor ~ulfonic acid and an additional S00 ml of acetone. Addition caused th~
temperature of the solution to ri~e to 50~C. The stirred solution was now seeded with 100 mg of (+)-~-~2-[acetyl(l-methylethyl)amino]ethyl]-~-t2-chlorophenyl)-l-piperidinebutanamide (-)-cam p orsulfonic acid salt and stirring was continued overnight.
The resulting ~ine particle crystalline product was filtered, washed with acQtone, and pulled ~y under N2. The filtrate containing an enriched mixture Of t-]-~-~2-tacetyl(l-~ethylethyl)aminoethyl~-~-(2-chlorophenyl)-1-piperidinebutanamide(-)camphorsulphonic acid salt is used in Example 2.
WO93~13087 2 1 2 2 5 8 ~ PCT/US92/1~20 _ g _ Drying of the product in a vacuum o~en at 50C
overnight gave 437 g of the salt. The salt had the following elemental analysis:
Required for ~H50ClN306S: c, 60.03; H, 7.87; N, 6.56;
Cl, 5.54; S, 5.01 Found: C, 60.06; H, 7.93; N, 6.59; Cl, 5.28; S, 5.14 m~p. 191.5-193C.
Step B
The product of Step A (436 g) was dissolved in 1500 ml of water. To this solution was added 2000 ml of methylene chloride and 92 ml of 29.4% ammonium hydroxide solution. The solution was now stirred for 15 minutes. The organic layer was separated, washed (2x) with 1 L ~f water, dried over anhydrous K~C03 and filtered. Btripping of the solvent under vacuum yielded 294 g of th~ crude product. The crude product was dissolved in 2 L of refluxing ethyl acetate and filtered while hot. The filtrate was transferred to a flask equipped with a magnetic stirring bar and stirred. Seeding of the filtrates with t+]-~-[2-racetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide caused the product to crystallize as a thick slurry. Stirring was discontinued and the slurry was allowed to stand o~ernight. The slurry was broken up, filtered and washed with 200 ml of ethyl acetate. The product was pulled dry and then dried in a vacuum at 50C. Tbis procedure gave 239 g of the title product.
Concentration of the filtrates gave additional ~+]--r 2-ta~ètyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide for an overall yield of 70%.
s The title product had the following elemental analysis:
WO g3/13087 PC~/US92/10020 2122584 - lo-Required for C22H34ClN30~: C, 64.77; H, 8.40; N, 10.30;
Cl, 8.69 Found: C, 64.73; H, 8.58; N, 10.20; Cl, 8.76 Specific Rotation: t~r~D25S+4 . go (C=1 in CHCl3) .
2i2`2~8~
WO93/1~87 PCT/US9~/10020 EXAMPLE 2 (46562) Preparation of 2-[acetyltl-methylethyl) amino]ethyl]-~ t2-chlorophenyl)-l-piperidinebutanamide O
~_N~
Cl St~p ~
The filtrate from example l containing an enriched ~ample of [-]-~-t2-[acetyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-1-piperidinebutanamide(-)-camphorsulphonic acid salt was concentrated to a solid weighing 613 g. The material was taken up in 1500 ml of water then made basic with ammonium hydroxide (100 ml). The mixture was extracted with two 700 ml portions of methylene chloride. The organic layers were drisd over K2C03 and filtered. The filtrate was concentrated to pro~ide 417 g of an enriched sample of ~ t2-[acetyl(1-methylethyl)amino]ethyl]-~-(2-chlorophenyl)-l-piperidinebutanamide. To this product in 2.0 L of acetone with stirring is added (+)-camphorsulfonic acid (207 g). The solution is seeded wi~h (-~-~-t2-tac~tyl(l-methylethyl)amino]ethyl]-~-(2-chlorophenyl~-1-piperidinebutanamide(+)-camphorsulfonic acid and an additional 500 ml of acetone is added.
Stirring was continued overnig~t. The resulting fine W093/130~ PCT/US92/1~20 2122~8~ - 12 -particle crystalline product was filtered, washed with acetone, and pulled dry under N2. Drying of the product in a vacuum oven at 50C overnight gave 404 g of the salt.
m.p. 190-193C.
Step B
The product of Step A (404 g) was dissolved in 1200 ml of water. To this solution was added 1400 ml of methylene chloride ~nd 120 ml of 29.4% ammonium hydroxide solution. The solution was now stirred ~or 15 minutes. The organic layer was separated, washed (2x) with 1 L of water, dried over anhydrous K2Co3 and filtered. Stripping of the solvent under vacuum yielded 335 g of the crude proclct. The crude product was dissolved in 2 L of refluxing ethyl acetate and filtered hot. The filtrates were transferred to a flask equipped with a magnetic stirring bar and stirred. Seeding of the filtrates with [~ -t2-E acetyl~l-methylethyl)amino]ethyl]-~-~2-chlorophenyl)-l-piperidinebutanamide cau~ed the product to crystallize as a thick slurry. Stirring was diccontinued and the slurry was allowed to stand overnight~ The slurry was broken up, filtered and washed with 200 ml of ethyl acetate. The product was pulled dry and then dried in a vacuum over at 50C.
This procedure gave 255 g of the title product.
The title product had the following elemental analysis:
Required for C~H~ClN302: C, 64.77; ~, 8.40; N, 10.30;
Cl, 8.~9 Found: C, 64.7~; H, ~.58; N, 10.20; Cl, 8.76 Specific Rotation: ~]D~=-5-4 (C=l in CHCl3).
Claims (3)
1. A process for the resolution of [?]-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide which has the following structural formula (?) into [?]-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide which has the following structural formula (+) and [-]-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide which has the following structural formula (-) comprising the steps of a) treating [?]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide with (1R)-(-)-10-camphor sulfonic acid in the presence of a solvent to give [+]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (-)-camphorsulfonic acid salt;
b) treating [+]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (-)-camphorsulfonic acid salt of step a with base to give [+]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide;
c) treating the filtrates of step b with base to give a mixture enriched in [-]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide;
d) treating the enriched mixture of step c with (+)-camphorsulfonic acid in the presence of a solvent to give [-]-.alpha.-[2-[acetyl(1-methylethyl)aminoethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (+)-camphorsulfonic acid salt;
and e) treating [-]-.alpha.-[2-[acetyl(1-methylethyl) aminoethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (+)-camphorsulfonic acid salt of step d with base to give [-]-.alpha.-[2-[acetyl(1-methylethyl) aminoethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide.
b) treating [+]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (-)-camphorsulfonic acid salt of step a with base to give [+]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide;
c) treating the filtrates of step b with base to give a mixture enriched in [-]-.alpha.-[2-[acetyl(1-methylethyl) amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide;
d) treating the enriched mixture of step c with (+)-camphorsulfonic acid in the presence of a solvent to give [-]-.alpha.-[2-[acetyl(1-methylethyl)aminoethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (+)-camphorsulfonic acid salt;
and e) treating [-]-.alpha.-[2-[acetyl(1-methylethyl) aminoethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide (+)-camphorsulfonic acid salt of step d with base to give [-]-.alpha.-[2-[acetyl(1-methylethyl) aminoethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide.
2. The process according to Claim 1 wherein the solvent is acetone.
3. The process according to Claim 1 wherein the base is ammonium hydroxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/811,182 | 1991-12-20 | ||
| US07/811,182 US5276155A (en) | 1991-12-20 | 1991-12-20 | Process for the resolution of (±)-α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2122584A1 true CA2122584A1 (en) | 1993-07-08 |
Family
ID=25205801
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002122584A Abandoned CA2122584A1 (en) | 1991-12-20 | 1992-11-27 | A process for the resolution of (+-)-.alpha.-[2-[acetyl(1-methylethyl)amino]ethyl]-.alpha.-(2-chlorophenyl)-1-piperidinebutanamide |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5276155A (en) |
| EP (1) | EP0619816A1 (en) |
| JP (1) | JPH07502513A (en) |
| AU (1) | AU3143693A (en) |
| CA (1) | CA2122584A1 (en) |
| WO (1) | WO1993013087A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0585500A1 (en) * | 1992-09-04 | 1994-03-09 | Merrell Dow Pharmaceuticals Inc. | Diaryl piperazineacetamides as antimuscarinic agents |
| US5731435A (en) * | 1995-05-03 | 1998-03-24 | G. D. Searle & Co. | Process for the preparation of heterocyclic alkylamide derivatives |
| DE19927412A1 (en) * | 1999-06-16 | 2000-12-21 | Bayer Ag | Process for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane |
| CA2285877A1 (en) * | 1999-10-15 | 2001-04-15 | Ibm Canada Limited-Ibm Canada Limitee | System and method for capturing document style by example |
| CA2955055C (en) * | 2017-01-17 | 2020-08-11 | Alwin Manufacturing Co., Inc. | Dispenser with noise dampener |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4639524A (en) * | 1984-07-09 | 1987-01-27 | G. D. Searle & Co. | Monobasic disobutamide derivatives |
| US5097035A (en) * | 1984-07-09 | 1992-03-17 | G. D. Searle & Co. | Monobasic disobutamide derivatives |
-
1991
- 1991-12-20 US US07/811,182 patent/US5276155A/en not_active Expired - Fee Related
-
1992
- 1992-11-27 WO PCT/US1992/010020 patent/WO1993013087A1/en not_active Application Discontinuation
- 1992-11-27 CA CA002122584A patent/CA2122584A1/en not_active Abandoned
- 1992-11-27 EP EP92925349A patent/EP0619816A1/en not_active Ceased
- 1992-11-27 JP JP5511290A patent/JPH07502513A/en active Pending
- 1992-11-27 AU AU31436/93A patent/AU3143693A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0619816A1 (en) | 1994-10-19 |
| US5276155A (en) | 1994-01-04 |
| WO1993013087A1 (en) | 1993-07-08 |
| AU3143693A (en) | 1993-07-28 |
| JPH07502513A (en) | 1995-03-16 |
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| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 19971127 |