WO2007012964A1 - Preparation of alkylpiperazinylphenyl compounds by classical resolution - Google Patents
Preparation of alkylpiperazinylphenyl compounds by classical resolution Download PDFInfo
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- WO2007012964A1 WO2007012964A1 PCT/IB2006/002115 IB2006002115W WO2007012964A1 WO 2007012964 A1 WO2007012964 A1 WO 2007012964A1 IB 2006002115 W IB2006002115 W IB 2006002115W WO 2007012964 A1 WO2007012964 A1 WO 2007012964A1
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- benzyl
- methyl
- piperazin
- pyrrolidin
- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
Definitions
- the present invention relates to novel methods for the optical resolution of racemic alkylpiperazinylphenyl compounds that include selective 5HT 1D antagonists. They are useful in treating or preventing depression, anxiety, migraine, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT 1 agonist or antagonist is indicated.
- 5HT 1D antagonists include selective 5HT 1D antagonists. They are useful in treating or preventing depression, anxiety, migraine, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT 1 agonist or antagonist is indicated.
- the present invention relates to a process for the optical resolution of a racemic mixture of the compound of formula I
- G 1 wherein Y is CH or N and R 3 is (CrCeJalkyl-, (C r C 6 )hydroxyalkyl- or (C 4 -C 8 )hydroxycycloalkyl- by (i) mixing a solution of the compound of formula I in a reaction inert solvent with (+)-di-p- toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric acid to form a precipitate of a (+)-di-p- toluoyl-D-tartaric acid salt or a (-)-di-p-toluoyl-L-tartaric acid salt enriched with an enantiomer of compound I and a solution of (+)-di-p-toluoyl-D-tartaric acid salt or (-)-di-p-toluoyl-L-tartaric acid salt enriched with the antipode of the enanti
- the antipode enriched salt is recovered by concentrating the aforesaid solution of antipode enriched salt.
- an enantiomer of compound I or an enantiomerically enriched mixture of compound I is prepared by treating the aforesaid enantiomerically enriched (+)-di-p-toluoyl-D-tartaric acid salt or (-)-di- p-toluoyl-L-tartaric acid salt of compound I with a base.
- the antipode of the aforesaid enantiomer of compound I or an enantiomeric mixture of compound I enriched with the aforesaid antipode is prepared by treating the antipode enriched salt with a base.
- a racemic mixture of the compound of formula I is prepared by treating an enantiomer of compound I or an enantiomerically enriched mixture of compound I, or the antipode of the aforesaid enantiomer of compound I or an enantiomeric mixture of compound I enriched with the aforesaid antipode with a strong base. By resolving the racemic mixture thereby producing a less desired enantiomer that can be converted into one that is more desirable.
- the process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein R 1 is methyl, X is CH 2 , n is 1 and R 2 is selected from hydrogen or the group G 1 wherein Y is CH or N and R 3 is 1-ethyl-1 -hydroxy- propyl, 2-methoxypropan-2-yl or 1-hydroxy-cyclobutyl.
- the process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein R 1 is methyl, X is O, n is 2 and R 2 is the group G 1 wherein Y is CH and R 3 is tertiary-butyl.
- the process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein R 1 , X, n, R 2 , and the variables of G 1 have any definition discussed herein.
- the process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein the compound is any one or more of the following:
- the process of the present invention also relates to a process for the preparation of an enantiomer, or a mixture of enantiomers enriched with one enantiomer, from a solution of the corresponding racemate wherein said racemate is selected from any one or more of the following:
- the process of the present invention also relates to a process for the preparation of an enantiomer, or a mixture of enantiomers enriched with one enantiomer, from a solution of the corresponding racemate wherein said racemate is selected from any one or more of the following:
- the present invention also relates to a process wherein an enantiomeric compound selected from the group consisting of any one or more of the following:
- 3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; is (i) treated with a strong base to produce a racemate and (ii) the racemate is treated with (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric to form a salt containing an excess of said antipode or an excess of said enantiomeric compound.
- the process of the present invention also relates to a process for the racemization of an (R) or (S) enantiomer of the compound of formula I, comprising treating a solution of the enantiomer, or an enantiomerically enriched mixture thereof, or a salt thereof, in a reaction inert solvent with a strong base.
- the process may further comprise using a solvent selected from methanol, ethanol, 2-propanol, fe/t-butanol or THF, or mixtures thereof, and the strong base is selected from the group consisting of potassium terf-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide, and wherein the enantiomer of the compound of formula I, or the enantiomerically enriched mixture thereof, or a salt thereof, is treated for about 2 to about 24 hours.
- the enantiomer or enantiomeric mixture thereof or salt thereof used in this process is selected from the group consisting of any one or more of the following:
- enantiomerically enriched mixture or “enantiomerically enriched” as used herein refer to mixtures of the (R) and (S) enantiomers of the compound of formula I or salts thereof having an excess of either the (R) or the (S) enantiomer of the compound of formula I.
- enantiomer refers to an optical isomer of the compound of formula I having either the (R) or the (S) stereochemical configuration.
- antipode or “optical antipode” as used herein refer to an optical isomer of the compound of formula I having a stereochemical configuration opposite to that of an enantiomer of the compound of formula I.
- the antipode has the (S) stereochemical configuration
- the antipode has the (R) stereochemical configuration.
- reaction conditions for all reaction schemes include an inert atmosphere commonly used in the art such as nitrogen or argon.
- Scheme 1 refers to preparation of the enantiomerically enriched (+)-di-p-toluoyl-D- tartaric acid or (-)-di-p-toluoyl-L-tartaric salts of the compound of formula I and the free base thereof.
- step 1 of Scheme 1 the enantiomerically enriched (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric salt of the compound of formula I is prepared from the racemic mixture of the compound of formula I by treating said racemic mixture with about 0.5 mole to about 2.0 molar equivalents, preferably about an equimolar amount of either (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric acid in a suitable solvent selected from methanol, ethanol, 2- propanol, acetone, methyl ethyl ketone, and acetonitrile either as a single solvent or a mixture and either in the presence or absence of water at about 20 0 C to about 80 0 C, preferably about 25°C to about 70 0 C, for about 1 hour to about 55 hours.
- (+)-di-p-toluoyl-D-tartaric acid salt When the (+)-di-p-toluoyl-D-tartaric acid salt is formed, one enantiomer remains in solution and the salt of the other enantiomer precipitates. When the (-)-di-p-toluoyl-/.-tartaric acid salt is formed, the opposite enantiomer remains in solution and the salt of the other enantiomer precipitates.
- the enantiomerically enriched salt is collected at about room temperature.
- the enantiomeric excess achieved by this step ranges from about 65% to about 100%. The enantiomeric excess can be evaluated using methods known in the art, such as the method disclosed in Enantiomers.
- a compound of formula I is resolved using (+)-di-p-toIuoyl-D-tartaric acid, producing a salt with an enantiomeric excess of at least about 65%.
- a portion of the undesired enantiomer can be crystallized using (-)-di-p-toluoyl-L-tartaric acid, producing a salt with an enantiomeric excess of at least about 65%.
- the mother liquors, enriched in the desired enantiomer can be converted to the desired enantiomer with an optical purity of at least about 90% in the final product.
- step 2 of Scheme 1 the compound of formula I enriched with either the R enantiomer or the S enantiomer is prepared from the enantiomerically enriched (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric salt of the compound of formula I by treatment with an aqueous inorganic base, such as NaOH, KOH, Na 2 CO 3 , or K 2 CO 3 and the like, in a solvent such as dichloromethane, toluene, diisopropyl ether, methyl ferf-butyl ether, preferably methyl fert-butyl ether to produce a pH that is greater than about 8, and concentration of the organic layer.
- an aqueous inorganic base such as NaOH, KOH, Na 2 CO 3 , or K 2 CO 3 and the like
- a solvent such as dichloromethane, toluene, diisopropy
- Scheme 2 refers to preparation of the racemate of a compound of formula I from an enantiomer of the compound of formula I or a mixture containing an excess of either the R enantiomer or S enantiomer of the compound of formula I.
- step 1 of Scheme 2 an enantiomeric compound of formula I, or an enantiomeric mixture enriched with either the R or S enantiomer of the compound of formula I, in the form of either the free base or a salt thereof, is dissolved in a solvent such as methanol, ethanol, 2- propanol, fert-butanol or THF, or mixtures thereof, at a temperature from about room temperature and about the reflux temperature, preferably about 65°C, and is treated with a base such as potassium or sodium terf-butoxide, sodium methoxide or sodium ethoxide, preferably potassium ferf-butoxide, and stirred for about 2 to about 24 hours, preferably about 15 hours, to afford the racemic compound of formula I.
- the process of Scheme 2 is useful in converting a less preferable enantiomer to a more preferable enantiomer.
- the process of Scheme 1 is then used to separate the more preferable enantiomer from the racemic mixture generated by the process of
- Example 1 (42.7 mg, 98:2 ratio by HPLC, 52% of theory).
- IR 3408, 1719, 1611 , 1266, 1107, 753 cm "1 .
- (+)-Di-p-toluoyl-D-tartaric acid (92.0 mg, 0.237 mmol) was added to 4-(4-terf-butyl- phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyI]-morpholin-3-one (100 mg, 0.237 mmol) in methanol (1.5 ml). The solution was stirred at room temperature for 1 day. The white solids were filtered to give Example 2 (58.9 mg, 95:5 ratio by HPLC, 63% of theory). IR: 3509, 1719, 1267, 1062, 995 cm '1 .
- (+)-Di-p-toluoyl-D-tartaric acid (30.74 g, 75.57 mmol) was added as a solid in portions. The mixture was stirred at 58°C for 5 hours and stirred at room temperature for two days. The white solids were filtered to give Example 3 (31.74 mg, 94:6 ratio by HPLC, 96% of theory). IR: 3413, 1715, 1611 , 1266, 1107, 754 cm "1 .
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Abstract
The present invention relates to a novel method for the optical resolution of racemic alkylpiperazinylphenyl compounds that include selective 5HTiD antagonists useful in treating or preventing depression, anxiety, migraine, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1 agonist or antagonist is indicated having the formula (I), wherein X, R1, and R2 have the definitions provided herein.
Description
PREPARATION OF ALKYLPIPERAZINYLPHENYL COMPOUNDS BY CLASSICAL
RESOLUTION Background Of The Invention
The present invention relates to novel methods for the optical resolution of racemic alkylpiperazinylphenyl compounds that include selective 5HT1D antagonists. They are useful in treating or preventing depression, anxiety, migraine, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1 agonist or antagonist is indicated.
Summary Of The Invention
The present invention relates to a process for the optical resolution of a racemic mixture of the compound of formula I
In another aspect of the resolution process of the present invention, the antipode enriched salt is recovered by concentrating the aforesaid solution of antipode enriched salt. In yet another aspect of the resolution process of the present invention, an enantiomer of compound I or an enantiomerically enriched mixture of compound I is prepared by treating the aforesaid enantiomerically enriched (+)-di-p-toluoyl-D-tartaric acid salt or (-)-di- p-toluoyl-L-tartaric acid salt of compound I with a base.
In a further aspect of the resolution process of the present invention, the antipode of the aforesaid enantiomer of compound I or an enantiomeric mixture of compound I enriched with the aforesaid antipode is prepared by treating the antipode enriched salt with a base.
In a still further aspect of the process of the present invention, a racemic mixture of the compound of formula I is prepared by treating an enantiomer of compound I or an enantiomerically enriched mixture of compound I, or the antipode of the aforesaid enantiomer of compound I or an enantiomeric mixture of compound I enriched with the aforesaid antipode with a strong base. By resolving the racemic mixture thereby producing a less desired enantiomer that can be converted into one that is more desirable. The process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein R1 is methyl, X is CH2, n is 1 and R2 is selected from hydrogen or the group G1 wherein Y is CH or N and R3 is 1-ethyl-1 -hydroxy- propyl, 2-methoxypropan-2-yl or 1-hydroxy-cyclobutyl.
The process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein R1 is methyl, X is O, n is 2 and R2 is the group G1 wherein Y is CH and R3 is tertiary-butyl.
The process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein R1, X, n, R2, and the variables of G1 have any definition discussed herein. The process of the present invention in all of its aspects relates to the optical resolution of the compound of formula I wherein the compound is any one or more of the following:
3(R)-I -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; 3(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(f?)-4-(4-terf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
2(S)-4-(4-terf-Butyl-phenyl)-2-[2-(4-methyI-piperazin-1-yl)-benzyl]-morpholin-3-one;
3(f?)-1 -[6-(1 -Ethyl- 1 -hydroxy-propyl)-pyridin-3-yl]-3-|;2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyI]-pyrrolidin-2-one; 3(f?)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; using any method discussed herein.
The process of the present invention also relates to a process for the preparation of an enantiomer, or a mixture of enantiomers enriched with one enantiomer, from a solution of the corresponding racemate wherein said racemate is selected from any one or more of the following:
(R)1(S)-I -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; (R),(S)-4-(4-terf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1 -yl)-benzyl]-morpholin-3-one;
(R)1(S)-I -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one;
(R),(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
(R),(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; comprising (i) treating said racemate with (+)-di-p-toluoyl-D-tartaric acid to form a precipitate of the corresponding (+)-di-p-toluoyl-D-tartaric acid salt wherein said salt is enriched with the corresponding enantiomer selected from any one or more of the following:
3(R)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(S)-4-(4-ferf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
3(R)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-[2-(4-Methyi-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and 3(R)-3-(2-(4-Methylpiperazin-1 -yl)benzyl)-1 -(4-(2-methoxypropan-2- yl )phenyl )pyrrolid in-2-one; and (ii) treating said salt with a base.
The process of the present invention also relates to a process for the preparation of an enantiomer, or a mixture of enantiomers enriched with one enantiomer, from a solution of the corresponding racemate wherein said racemate is selected from any one or more of the following:
1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-pyrrolidin-2- one;
4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
3-[2-<4-Methyl-piperazin-1 -yl)-benzyl]-pyrrolidin-2-one; and
-A-
3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2-yl)phenyl)pyrroIiclin-2- one; comprising (i) treating said racemate with (-)-di-p-toluoyl-L-tartaric acid to form a precipitate of the corresponding (-)-di-p-toluoyl-L-tartaric acid salt wherein said salt is enriched with the corresponding enantiomer selected from any one or more of the following:
3(S)-1 -[4-(1 -Hydroxy-cydobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(R)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
3(S)-1 -[6-(1 -Ethyl- 1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; and (ii) treating said salt with a base. The present invention also relates to a process wherein an enantiomeric compound selected from the group consisting of any one or more of the following:
3(R)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
3(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(R)-4-(4-teAf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
2(S)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
3(f?)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one; 3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyI-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yI)-benzyl]-pyrrolidin-2-one;
3(f?)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; is (i) treated with a strong base to produce a racemate and (ii) the racemate is treated with (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric to form a salt containing an excess of said antipode or an excess of said enantiomeric compound.
The process of the present invention also relates to a process for the racemization of an (R) or (S) enantiomer of the compound of formula I, comprising treating a solution of the
enantiomer, or an enantiomerically enriched mixture thereof, or a salt thereof, in a reaction inert solvent with a strong base. The process may further comprise using a solvent selected from methanol, ethanol, 2-propanol, fe/t-butanol or THF, or mixtures thereof, and the strong base is selected from the group consisting of potassium terf-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide, and wherein the enantiomer of the compound of formula I, or the enantiomerically enriched mixture thereof, or a salt thereof, is treated for about 2 to about 24 hours. The enantiomer or enantiomeric mixture thereof or salt thereof used in this process is selected from the group consisting of any one or more of the following:
3(R)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
3(S)- 1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(f?)-4-(4-fert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
2(S)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 3(R)- 1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; 3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one;
3(R)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yI)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one. The terms "enantiomerically enriched mixture" or "enantiomerically enriched" as used herein refer to mixtures of the (R) and (S) enantiomers of the compound of formula I or salts thereof having an excess of either the (R) or the (S) enantiomer of the compound of formula I.
The term "enantiomer" as used herein refers to an optical isomer of the compound of formula I having either the (R) or the (S) stereochemical configuration. The terms "antipode" or "optical antipode" as used herein refer to an optical isomer of the compound of formula I having a stereochemical configuration opposite to that of an enantiomer of the compound of formula I. Thus, if the enantiomer of the compound of formula I has the (R) stereochemical configuration, the antipode has the (S) stereochemical configuration and if the enantiomer of the compound of formula I has the (S) stereochemical configuration, the antipode has the (R) stereochemical configuration.
Detailed Description of the Invention
EΞxcept where otherwise stated, X, R1, R2, n, G1, Y and R3 in the reaction schemes and discussions that follow are defined as above. Unless otherwise stated reaction conditions for all reaction schemes include an inert atmosphere commonly used in the art such as nitrogen or argon.
Scheme 1 refers to preparation of the enantiomerically enriched (+)-di-p-toluoyl-D- tartaric acid or (-)-di-p-toluoyl-L-tartaric salts of the compound of formula I and the free base thereof.
In step 1 of Scheme 1, the enantiomerically enriched (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric salt of the compound of formula I is prepared from the racemic mixture of the compound of formula I by treating said racemic mixture with about 0.5 mole to about 2.0 molar equivalents, preferably about an equimolar amount of either (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric acid in a suitable solvent selected from methanol, ethanol, 2- propanol, acetone, methyl ethyl ketone, and acetonitrile either as a single solvent or a mixture and either in the presence or absence of water at about 200C to about 800C, preferably about 25°C to about 700C, for about 1 hour to about 55 hours. When the (+)-di-p-toluoyl-D-tartaric acid salt is formed, one enantiomer remains in solution and the salt of the other enantiomer precipitates. When the (-)-di-p-toluoyl-/.-tartaric acid salt is formed, the opposite enantiomer remains in solution and the salt of the other enantiomer precipitates. The enantiomerically enriched salt is collected at about room temperature. The enantiomeric excess achieved by this step ranges from about 65% to about 100%. The enantiomeric excess can be evaluated using methods known in the art, such as the method disclosed in Enantiomers. Racemates and Resolutions J Jacques, et al., John Wiley & Sons, New York, 1981. If the salt of the desired enantiomer remains is solution, it can be recovered by evaporation of the solvent. In the preferred embodiment of the process of the present invention, a compound of formula I is resolved using (+)-di-p-toIuoyl-D-tartaric acid, producing a salt with an enantiomeric excess of at least about 65%. Alternatively, a portion of the undesired enantiomer can be crystallized using (-)-di-p-toluoyl-L-tartaric acid, producing a salt with an enantiomeric excess of at least about 65%. The mother liquors, enriched in the desired enantiomer, can be converted to the desired enantiomer with an optical purity of at least about 90% in the final product.
In step 2 of Scheme 1 , the compound of formula I enriched with either the R enantiomer or the S enantiomer is prepared from the enantiomerically enriched (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-L-tartaric salt of the compound of formula I by treatment with an aqueous inorganic base, such as NaOH, KOH, Na2CO3, or K2CO3 and the like, in a solvent such as dichloromethane, toluene, diisopropyl ether, methyl ferf-butyl ether, preferably methyl
fert-butyl ether to produce a pH that is greater than about 8, and concentration of the organic layer.
SCHEME 1
DTTA = Di-p-toluoyl-tartaric acid
Scheme 2 refers to preparation of the racemate of a compound of formula I from an enantiomer of the compound of formula I or a mixture containing an excess of either the R enantiomer or S enantiomer of the compound of formula I.
In step 1 of Scheme 2 an enantiomeric compound of formula I, or an enantiomeric mixture enriched with either the R or S enantiomer of the compound of formula I, in the form of either the free base or a salt thereof, is dissolved in a solvent such as methanol, ethanol, 2- propanol, fert-butanol or THF, or mixtures thereof, at a temperature from about room temperature and about the reflux temperature, preferably about 65°C, and is treated with a base such as potassium or sodium terf-butoxide, sodium methoxide or sodium ethoxide, preferably potassium ferf-butoxide, and stirred for about 2 to about 24 hours, preferably about 15 hours, to afford the racemic compound of formula I. The process of Scheme 2 is useful in converting a less preferable enantiomer to a more preferable enantiomer. The process of Scheme 1 is then used to separate the more preferable enantiomer from the racemic mixture generated by the process of Scheme 2.
SCHEME 2
Enantiomerically enriched Racemic I I or salt of I
EXAMPLES Example 1
3(R)-1 -[4-(I -Hvdroxy-cyclobutvn-phenvn-3-r2-(4-methyl-piperazin-1 -vD-benzyll- pyrrolidin-2-one (+)-di-p-toluoyl-D-tartaric acid (+)-Di-p-toluoyl-D-tartaric acid (78.4 mg, 0.203 mmol) was added to 1-[4-(1-hydroxy- cyclobutyl)-phenyl]-3-[2-(4-methyI-piperazin-1-yI)-benzyl]-pyrrolidin-2-one (85.2 mg, 0.203 mmol) in a 50/50 mixture of 2-propanol and acetone (2.1 ml). The solution was stirred at room temperature for 2 days. The white solids were filtered to give Example 1 (42.7 mg, 98:2 ratio by HPLC, 52% of theory). IR: 3408, 1719, 1611 , 1266, 1107, 753 cm"1. 1H (400 MHz, CD3OD): δ 1.64-1.73 (m, 1), 1.80-1.89 (m, 1 ), 1.94-2.04 (m, 1), 2.05-2.22 (m, 1), 2.30-2.38 (m, 2), 2.38 (s, 6), 2.46-2.53 (m, 2), 2.67 (dd, 1 , J = 10.0, 13.7), 2.81 (s, 3), 2.96-3.30 (m, 6), 3.33 (dd, 2, J = 4.2, 13.7), 3.66-3.78 (m, 2), 5.88 (s, 2), 7.09 (d, 1 , J = 7.5), 7.12 (d, 1, J = 7.5), 7.22 (dt, 1, J = 1.2, 7.5), 7.26 (d, 4, J = 8.3), 7.26-7.28 (m, 1), 7.52 (d, 2, J = 8.7), 7.59 (d, 2, J = 8.7), 7.99 (d, 4, J = 8.3). 13C NMR (100 MHz, CD3OD): δ 12.60, 20.50, 24.46, 32.48, 36.69, 42.34, 44.75, 47.30, 53.91, 73.63, 75.90, 120.45, 121.04, 125.40, 125.50, 127.13, 127.73, 129.01, 129.87, 130.76, 135.26, 138.20, 143.59, 144.32, 150.14, 166.16, 170.50, 176.80.
Example 2 2(S)-4-(4-te/t-Butyl-phenvπ-2-r2-(4-methyl-piperazin-1-vπ-benzvn-morpholin-3-one (+) di-p-toluoyl-P-tartaric acid
(+)-Di-p-toluoyl-D-tartaric acid (92.0 mg, 0.237 mmol) was added to 4-(4-terf-butyl- phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyI]-morpholin-3-one (100 mg, 0.237 mmol) in methanol (1.5 ml). The solution was stirred at room temperature for 1 day. The white solids were filtered to give Example 2 (58.9 mg, 95:5 ratio by HPLC, 63% of theory). IR: 3509, 1719, 1267, 1062, 995 cm'1. 1H (400 MHz, DMSOd6): δ 1.54-1.73 (m, 2), 1.81-1.89 (m, 1), 1.97- 1.99.(m, 1), 2.18-2.26 (m, 2), 2.33 (s, 9), 2.56 (s, 6), 2.61-2.65 (m, 1), 2.87-3.08 (m, 8), 3.13- 3.16 (m, 1 ), 3.64-3.67 (m, 2), 5.66 (s, 2), 6.95 (d, 1, J = 7.9), 7.06 (t, 1 , J = 7.1 ), 7.12 (t, 1 , J = 7.1), 7.24 (d, 1 , J = 7.1), 7.29 (d, 4, J = 7.9), 7.44 (d, 2, J = 8.7), 7.60 (d, 2, J = 8.3), 7.82 (d, 4, J = 7.9). 13C NMR (100 MHz, DMSOd6): δ 13.33, 21.88, 24.94, 32.32, 38.03, 44.42, 46.78, 50.56, 54.05, 72.66, 75.53, 119.45, 121.01, 125.17, 127.29, 127.90, 129.99, 130.01, 130.85, 135.62, 135.63, 143.98, 144.59, 151.16, 165.351 , 168.80, 175.63.
Example 3
3(ffl-1 -rβ-(1 -Ethyl-1 -hvdroxy-propyl)-pyridin-3-vn-3-r2-(4-methyl-piperazin-1 -vD-benzyli- pyrrolidin-2-one (+)-di-p-toluoyl-D-tartaric acid To acetonitrile (2000 mL) heated to 500C was added 1-[6-(1-ethyl-1-hydroxy-propyl)- pyridin-3-yl]-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one (34.74 g, 75.57 mmol). (+)-Di-p-toluoyl-D-tartaric acid (30.74 g, 75.57 mmol) was added as a solid in portions. The
mixture was stirred at 58°C for 5 hours and stirred at room temperature for two days. The white solids were filtered to give Example 3 (31.74 mg, 94:6 ratio by HPLC, 96% of theory). IR: 3413, 1715, 1611 , 1266, 1107, 754 cm"1. 1H (400 MHz, CD3OD): δ 0.67 (t, 6, J = 7.5), 1.76-1.97 (m, 5), 2.08-2.16 (m, 1), 2.37 (s, 6), 2.67 (dd, 1 , J = 13.7, 10.0), 2.82 (s, 3), 3.00- 3.36 (m, 7), 3.72-3.79 (m, 2), 5.88 (s, 2), 7.08-7.13 (m, 2), 7.18-7.28 (m, 2), 7.25 (d, 4, J = 8.3), 7.61 (d, 1 , J = 8.7), 7.99 (d, 4, J = 8.3), 8.07 (dd, 1 , J = 8.7, 2.5), 8.87 (d, 1, J = 2.1). 13C NMR (100 MHz, CD3OD): δ 6.91 , 20.50, 24.55, 32.41 , 34.10, 42.34, 44.39, 46.42, 53.93, 73.68, 77.57, 120.80, 121.10, 125.42, 127.14, 127.78, 127.95, 129.01, 129.87, 130.67, 134.73, 135.17, 139.19, 144.33, 150.12, 160.15, 166.18, 170.58, 177.25. Example 4
3(/?)-3-r2-(4-Methyl-piperazin-1-vO-benzvπ-PVrrolidin-2-one (+)-di-p-toluoyl-P-tartaric acid
To 3-[2-(4-methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one (21.12g, 77.26 mmol) in acetonitrile at 700C was added (+)-di-p-toluoyl-D-tartaric acid (29.86g, 77.26 mmol) portion- wise. The reaction mixture was allowed to cool to room temperature overnight. The white solids were filtered and washed with cold acetonitrile and dried to give Example 4 (19.85 g, 93:7 ratio by HPLC, 78% of theory). IR: 3398, 1717, 1611 , 1265, 1107, 753 cm'1. 1H (400 MHz, CD3OD): δ 1.70-1.79 (m, 1), 1.96-2.31 (m, 1), 2.37 (s, 6), 2.53 (dd, 1 , J = 10.4, 13.7), 2.73 (dq, 1 , J = 4.1 , 8.7), 2.83 (s, 3), 2.88-3.10 (m, 4), 3.19-3.26 (m, 4), 3.28-3.48 (m, 3), 5.89 (s, 2), 7.06 (d, 1 , J = 8.3), 7.10 (d, 1 , J = 7.5), 7.18 (dt, 1, J = 1.7, 7.9), 7.21-7.25 (m, 1), 7.25 (d, 4, J = 7.9), 7.99 (d, 4, J = 8.3). 13C NMR (100 MHz, CD3OD): δ 20.50, 26.89, 32.04, 40.37, 42.34, 42.44, 53.88, 73.63, 121.05, 125.35, 127.11 , 127.62, 129.02, 129.87, 130.62, 135.49, 144.36, 150.12, 166.17, 170.53, 181.19.
Example 5 Free basing of the salts
Each of the above salts (about 40-100 mg) was individually dissolved in an organic solvent (methyl tert-butyl ether, toluene or dichloromethane) (5 mL), the solution was washed with a base (1N aqueous sodium hydroxide or sodium bicarbonate, 2 times with 5 mL), brine
(5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford the corresponding free base.
Example 6 Racemization of (S)-1 -rβ-f1 -ethyl-1 -hvdroxy-propyl)-pyridin-3-vn-3-f2-(4-methyl- piperazin-1-v0-benzvπ-Pyrrolidirt-2-one
To a non-racemic mixture of (S)-1-[6-(1-ethyl-1-hydroxy-propyl)-pyridin-3-yl]-3-[2-(4- methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one (100 mg, 0.229 mmol) in THF (3 mL) was added potassium terf-butoxide (25.7 mg, 0.229 mmol). The solution was stirred at room temperature overnight. The mixture was concentrated and a mixture of isopropyl acetate and
hexanes was added. Solids precipitated and were filtered to afford racemic 1-[6-(1-ethyl-1- hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-pyrrolidin-2-one (86 mg, 86% yield). The product was identical to the starting material of Example 3.
Example 7 3(R)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2-yl)phenyl)pyrrolidin-
2 -one (+) di-p-toluoyl-D-tartaric acid
(+) Di-p-toluoyl-D-tartaric acid (43.5 mg, 0.114 mmol) was added to 3-(2-(4- methyIpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2-yl)phenyl)pyrrolidin-2-one (94.8 mg, 0.225 mmol) in acetonitrile (0.95 ml). The mixture was stirred at room temperature for 2 days. The precipitate were filtered and washed with cold acetonitrile to give Example 7 (16.6 mg,
98.7:1.3 ratio by HPLC, 18% of theory). 1 H (400 MHz, DMSOd6): δ 1.41 (s, 6), 1.66-1.73 (m, 1), 1.97-2.02 (m, 1), 2.33 (s, 6), 2.55 (s, 3), 2.65 (dd, 1, J = 13.7, 10.0), 2.80-3.02 <m, 9), 2.92 (s, 3), 3.18 (dd, 1, J = 13.7, 3.7), 3.66-3.70 (m, 2), 5.64 (s, 2), 6.99 (d, 1 , J = 7.9), 7.01-7.07 (m, 1), 7.16 (dt, 1 , J = 1.2, 7.5), 7.25 (dd, 1 , J = 7.5, 1.2), 7.29 (d, 4, J = 8.3), 7.35 (d, 2, J = 8.7), 7.62 (d, 2, J = 8.7), 7.82 (d, 4, J = 7.9).
Claims
1. A process for the optical resolution of a racemic mixture of the compound of formula I,
G1 wherein Y is CH or N and R3 is (CrC6)alkyl-, 
or (C4- C8)hydroxycycloalkyl- comprising the steps of: (i) mixing a solution of the racemic mixture in a reaction inert solvent with (+)-di-p-toluoyl-D-tartaric acid or (-)-di-p-toluoyl-/.-tartaric acid to form a precipitate of a (+)-di-p-toluoyl-D-tartaric acid salt or a (-)-di-p-toluoyl-L-tartaric acid salt enriched with an enantiomer of compound I and a solution of (+)-di-p-toluoyl-D-tartaric acid salt or (-)-di-p-toluoyl-L-tartaric acid salt enriched with the antipode of the enantiomer, and (ii) separating the precipitate of enantiomerically enriched salt from the solution of antipode enriched salt.
2. The process according to claim 1 comprising the further step wherein an enantiomer of the compound of formula I or an enantiomerically enriched mixture of the compound of formula I is prepared by treating said enantiomerically enriched (+)-di-p-toluoyl- D-tartaric acid salt or (-)-di-p-toluoyl-Z.-tartaric acid salt of the compound of formula I in a solvent with an aqueous base to produce a pH that is greater than about 8.
3. The process according to claim 1 comprising the further step wherein said antipode enriched salt is recovered by concentrating the solution of antipode enriched salt.
4. The process according to claim 3 comprising the further step wherein the antipode or an enantiomeric mixture of the compound of formula I enriched with the antipode is prepared by treating the antipode enriched (+)-di-p-toluoyl-D-tartaric acid salt or (-)-di-p- toluoyl-L-tartaric acid salt of the compound of formula I in a solvent with an aqueous base to produce a pH that is greater than about 8.
5. The process according to claim 1 step (i) wherein the racemic mixture of the compound of formula I is selected from:
(R)1(S)-I -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; (R),(S)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
(R)1(S)-I -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
(R),(S)-3~[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and (R),(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyI)pyrrolidin-2-one; wherein the solvent is selected from the group consisting of methanol, ethanol, 2- propanol, acetone, methyl ethyl ketone, acetonitrile and mixtures thereof in the presence or absence of water; and wherein the precipitate of the (+)-di-p-toluoyl-D-tartaric acid salt is enriched with: 3(R)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(S)-4-(4-te/t-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 3(R)- 1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one; 3(R)-3-[2-(4-Methyl-piperazin-1 -yl)-benzyl]-pyrrolidin-2-one; and
3(R)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; or wherein the precipitate of the (-)-di-p-toluoyl-L-tartaric acid salt is enriched with: 3(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(R)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and 3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one.
6. The process of any of claims 1 to 5, wherein the precipitate is the (+)-di-p- toluoyl-D-tartaric acid salt and the antipode is the (-)-di-p-toluoyl-L-tartaric acid salt.
7. The process according to claim 3 wherein the racemic mixture is selected from:
(R)1(S)-I -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; (f?),(S)-4-(4-te/t-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
(R),(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyI)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrroIidin-2-one;
(R),(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and (R),(S)-3-(2-(4-Methylpiperazin-1 -yl)benzyl)-1 -(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; wherein the antipode enriched (+)-di-p-toluoyl-D-tartaric acid salt is enriched with:
3(R)- 1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; 2(S)-4-(4-terf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1 -yl)-benzyl]-morpholin-3-one;
3(f?)-1 -[6-(1 -Ethy!-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
3(R)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; or wherein the antipode enriched (-)-di-p-toluoyl-/.-tartaric acid salt is enriched with:
3(S)-1 -[4-(1 -Hydroxy-cyciobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(f?)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one.
8. The process according to claim 2 wherein the enantiomerically enriched (+)- di-p-toluoyl-D-tartaric acid salt is enriched with:
3(R)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(S)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 3(/?)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
3(f?)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; or wherein the enantiomerically enriched (-)-di-p-toluoyl-L-tartaric acid salt is enriched with an enantiomer selected from the group consisting of: 3(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(R)-4-(4-terf-Butyl-phenyI)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; wherein the solvent is selected from the group consisting of dichloromethane, toluene, diisopropyl ether and methyl fert-butyl ether, and the base is an aqueous inorganic base selected from the group consisting of NaOH, KOH, Na2CO3, and K2CO3.
9. The process according to claim 4 wherein the antipode enriched (+)-di-p- toluoyl-D-tartaric acid salt is enriched with: 3(f?)-1-[4-(1-Hydroxy-cyclobutyl)-phenyl]-3-[2-(4- methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; 2(S)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1 -yl)-benzyl]-morpholin-3-one;
3(f?)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and 3(R)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; or wherein the antipode enriched (-)-di-p-toluoyl-L-tartaric acid salt is enriched with an antipode selected from the group consisting of:
3(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; 2(R)-4-(4-te/t-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yI)-benzyl]-morpholin-3-one;
3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and 3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; wherein the solvent is selected from the group consisting of dichloromethane, toluene, diisopropyl ether and methyl terf-butyl ether, and the base is an aqueous inorganic base selected from the group consisting of NaOH, KOH, Na2CO3, and K2CO3.
10. The process according to claim 6 wherein the racemic mixture is treated with about 1 equivalent of (+)-di-p-toluoyl-D-tartaric acid or about 1 equivalent of (-)-di-p-toluoyl-L- tartaric acid, and stirred for about 2 hours to about 48 hours.
11. A process for the racemization of an (R) or (S) enantiomer of the compound of formula I
G1 wherein Y is CH or N and R3 is (C1-C6JaIKyI-, (C^CeJhydroxyalkyl- or (C4- C8)hydroxycycloalkyl- or salts thereof, comprising treating a solution of the enantiomer, or an enantiomerically enriched mixture thereof, or a salt thereof, in a reaction inert solvent with a strong base.
12. The process according to claim 11 wherein the solvent is selected from methanol, ethanol, 2-propanol, terf-butanol or THF, or mixtures thereof, and the strong base is selected from the group consisting of potassium terf-butoxide, sodium terf-butoxide, sodium methoxide and sodium ethoxide, and wherein the enantiomer of the compound of formula I, or the enantiomerically enriched mixture thereof, or a salt thereof, is treated for about 2 to about 24 hours.
13. The process according to claim 12 wherein the enantiomer or enantiomeric mixture thereof or salts thereof are enriched with an enantiomer selected from the group consisting of:
3(f?)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
3(S)-1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one; 2(f?)-4-(4-terf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
2(S)-4-(4-tert-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one; 3(f?)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrol id in-2-one; 3(S)-1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one;
3(S)-3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; 3(R)-3-(2-(4-Methylpiperazin-1 -yl)benzyl)-1 -(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one; and
3(S)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one.
14. The process according to any of claims 11 to 13 wherein the enantiomer is selected from the group consisting of:
3(R)- 1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]- pyrrolidin-2-one;
2(S)-4-(4-terf-Butyl-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzyl]-morpholin-3-one;
3(R)- 1 -[6-(1 -Ethyl-1 -hydroxy-propyl)-pyridin-3-yl]-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-pyrrolidin-2-one;
3(R)-3-t2-(4-Methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one; and
3(R)-3-(2-(4-Methylpiperazin-1-yl)benzyl)-1-(4-(2-methoxypropan-2- yl)phenyl)pyrrolidin-2-one.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70221905P | 2005-07-25 | 2005-07-25 | |
| US60/702,219 | 2005-07-25 |
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| WO2007012964A1 true WO2007012964A1 (en) | 2007-02-01 |
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| PCT/IB2006/002115 WO2007012964A1 (en) | 2005-07-25 | 2006-07-20 | Preparation of alkylpiperazinylphenyl compounds by classical resolution |
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| Country | Link |
|---|---|
| JP (1) | JP2007031433A (en) |
| AR (1) | AR054867A1 (en) |
| TW (1) | TW200716549A (en) |
| WO (1) | WO2007012964A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457231A (en) * | 2019-09-09 | 2021-03-09 | 上海医药工业研究院 | Racemization method of larotrytinib intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997036867A1 (en) * | 1996-03-29 | 1997-10-09 | Pfizer Inc. | Benzyl(idene)-lactam derivatives, their preparation and their use as selective (ant)agonists of 5-ht1a- and/or 5-ht1d receptors |
| EP1113015A1 (en) * | 1999-12-29 | 2001-07-04 | Pfizer Products Inc. | Optically active 3-((2-piperazinyl-phenyl)methyl)-1-(4-(trifluoromethyl)-phenyl)-2-pyrrolidinone compounds as 5-HT1D receptor selective antagonists |
| WO2005061491A2 (en) * | 2003-12-15 | 2005-07-07 | Pfizer Products Inc. | Aralkyl and aralkylidene heterocyclic lactams with affinity for 5-ht1 receptors |
-
2006
- 2006-07-20 WO PCT/IB2006/002115 patent/WO2007012964A1/en active Application Filing
- 2006-07-24 TW TW095126998A patent/TW200716549A/en unknown
- 2006-07-24 JP JP2006200748A patent/JP2007031433A/en active Pending
- 2006-07-25 AR ARP060103198A patent/AR054867A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997036867A1 (en) * | 1996-03-29 | 1997-10-09 | Pfizer Inc. | Benzyl(idene)-lactam derivatives, their preparation and their use as selective (ant)agonists of 5-ht1a- and/or 5-ht1d receptors |
| EP1113015A1 (en) * | 1999-12-29 | 2001-07-04 | Pfizer Products Inc. | Optically active 3-((2-piperazinyl-phenyl)methyl)-1-(4-(trifluoromethyl)-phenyl)-2-pyrrolidinone compounds as 5-HT1D receptor selective antagonists |
| WO2005061491A2 (en) * | 2003-12-15 | 2005-07-07 | Pfizer Products Inc. | Aralkyl and aralkylidene heterocyclic lactams with affinity for 5-ht1 receptors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457231A (en) * | 2019-09-09 | 2021-03-09 | 上海医药工业研究院 | Racemization method of larotrytinib intermediate |
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| JP2007031433A (en) | 2007-02-08 |
| AR054867A1 (en) | 2007-07-25 |
| TW200716549A (en) | 2007-05-01 |
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