WO2015087291A1 - 3-carboxy-4-(r)-phenylpyrrolydine-2-one salt and its use - Google Patents
3-carboxy-4-(r)-phenylpyrrolydine-2-one salt and its use Download PDFInfo
- Publication number
- WO2015087291A1 WO2015087291A1 PCT/IB2014/066846 IB2014066846W WO2015087291A1 WO 2015087291 A1 WO2015087291 A1 WO 2015087291A1 IB 2014066846 W IB2014066846 W IB 2014066846W WO 2015087291 A1 WO2015087291 A1 WO 2015087291A1
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- WO
- WIPO (PCT)
- Prior art keywords
- carboxy
- phenylpyrrolidine
- salt
- benzoyloxyquinuclidine
- water
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- Current invention is generally related to intermediates for preparation of medicaments, namely to a novel process for the synthesis of 3-carboxy-4-(i?)-phenylpyrrolidine-2-one.
- 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one may be converted by decarboxylation into known 4- (i?)-phenylpyrrolidine-2-one (Synthesis, (1991) 1023-1026), a useful starting material for preparation of N-carbamoylmethyl-4-(i?)-phenylpyrrolidine-2-one, which is known as the active enantiomer of the CNS agent Carphedon (WO2007104780).
- 3-carboxy-4-(i?)-phenylpyrrolidine-2-one forms a strongly crystalline salt with 3-(5)-benzoyloxyquinuclidine, which is not known for being used for separation of enantiomers.
- Said 3-(5)-benzoyloxyquinuclidine may be obtained by separation of the commercially available 3-(i?, ⁇ S)-benzoyloxyquinuclidine (INN: Benzoclidine), or by benzoylation of a commercially available 3-(5)-hydroxyquinuclidine, as it is described for the synthesis of racemate (Bioorg. &Med. Chem. Lett., 14, 3781-3784).
- novel strongly crystalline 3-carboxy-4-(i?)- phenylpyrrolidine-2-one salt with 3-(5)-benzoyloxyquinuclidine may be easily obtained from a process, well scalable for industrial manufacture.
- 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one salt with 3 -( ⁇ -benzoyl oxyquinuclidine is obtained in high yield and purity by reacting a racemic 3- carboxy-4-(i?,5)-phenylpyrrolidine-2-one with 3-(5)-benzoyloxyquinuclidine in a solvent, followed by recrystallization of the obtained crude salt.
- solvent for this reaction and recrystallization is selected from the group comprising water, methanol, propalol-1, propanol-2 and acetonitrile.
- the reaction of 3-carboxy-4-(i?,5)-phenylpyrrolidine-2-one with 3-(S)- benzoyloxyquinuclidine is performed in ethanol, and recrystallization of the 3-carboxy-4-(i?)- phenylpyrrolidine-2-one salt with 3-(5)-benzoyloxyquinuclidine is performed from water.
- 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one may be obtained from the said salt by protonation with a suitable mineral acid solution in water, in the preferred embodiment using hydrochloric acid.
- 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one which crystallizes from the solution may be further used without additional purification, but may also be recrystallized from water.
- the current invention provides a novel easy method for obtaining 3-carboxy-4-(i?)- phenylpyrrolidine-2-one from the racemate, by using a new resolution reagent in industrially applicable solvent.
- 3-Carboxy-4-(i?,5)-phenylpyrrolidine-2-one (210 g) was suspended in acetonitrile (520 ml). The suspension was heated to approx. 60 °C and 3-(5)-benzoyloxyquinuclidine (240 g) solution in acetonitrile (320 ml) was added upon stirring. The reaction mixture was stirred at this temperature for approx. 20 min and then was allowed to cool down to room temperature.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A novel method for obtaining 3-carboxy-4-(R)-phenylpyrrolidine-2-one from 3-carboxy-4- (R,S)-phenylpyrrolidine-2-one in which the racemic mixture is separated using 3-(S)- benzoyloxyquinuclidine.
Description
3-CARBOXY-4-(i?)-PHENYLPYRROLYDINE-2-ONE SALT AND ITS USE
Field of invention
Current invention is generally related to intermediates for preparation of medicaments, namely to a novel process for the synthesis of 3-carboxy-4-(i?)-phenylpyrrolidine-2-one.
Background of invention
3-Carboxy-4-(i?)-phenylpyrrolidine-2-one may be converted by decarboxylation into known 4- (i?)-phenylpyrrolidine-2-one (Synthesis, (1991) 1023-1026), a useful starting material for preparation of N-carbamoylmethyl-4-(i?)-phenylpyrrolidine-2-one, which is known as the active enantiomer of the CNS agent Carphedon (WO2007104780).
Separation of racemic 3-carboxy-4-phenylpyrrolidine-2-one by fractional crystallization of 3- carboxy-4-(i?)-phenylpyrrolidine-2-one cinchonidine salt is known in the art (Pol. J. Chem., 53 (1979) 435-446). However, this method is not applicable on an industrial scale because of the use of large amount of highly flammable solvents; it is time- and resources-consuming and is characterized by low and unstable yields.
An enzymatic synthesis of this optically active compound is known (LV13635 (2006)) but this method has several disadvantages like high cost and it is not suitable for large-scale production of this compound.
Taking into account that limitations of said methods cannot be negated, there is a need in development of a new suitable process, which can be used for industrial scale production and which is potentially of a high positive economic effect.
Description of invention
We have unexpectedly discovered, that 3-carboxy-4-(i?)-phenylpyrrolidine-2-one forms a strongly crystalline salt with 3-(5)-benzoyloxyquinuclidine, which is not known for being used for separation of enantiomers. Said 3-(5)-benzoyloxyquinuclidine may be obtained by separation of the commercially available 3-(i?,<S)-benzoyloxyquinuclidine (INN: Benzoclidine),
or by benzoylation of a commercially available 3-(5)-hydroxyquinuclidine, as it is described for the synthesis of racemate (Bioorg. &Med. Chem. Lett., 14, 3781-3784).
According to the current invention, novel strongly crystalline 3-carboxy-4-(i?)- phenylpyrrolidine-2-one salt with 3-(5)-benzoyloxyquinuclidine may be easily obtained from a process, well scalable for industrial manufacture. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one salt with 3 -(^-benzoyl oxyquinuclidine is obtained in high yield and purity by reacting a racemic 3- carboxy-4-(i?,5)-phenylpyrrolidine-2-one with 3-(5)-benzoyloxyquinuclidine in a solvent, followed by recrystallization of the obtained crude salt.
In the preferred embodiment, solvent for this reaction and recrystallization is selected from the group comprising water, methanol, propalol-1, propanol-2 and acetonitrile. In the most preferred embodiment, the reaction of 3-carboxy-4-(i?,5)-phenylpyrrolidine-2-one with 3-(S)- benzoyloxyquinuclidine is performed in ethanol, and recrystallization of the 3-carboxy-4-(i?)- phenylpyrrolidine-2-one salt with 3-(5)-benzoyloxyquinuclidine is performed from water.
3-Carboxy-4-(i?)-phenylpyrrolidine-2-one may be obtained from the said salt by protonation with a suitable mineral acid solution in water, in the preferred embodiment using hydrochloric acid. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one which crystallizes from the solution may be further used without additional purification, but may also be recrystallized from water.
Thus, the current invention provides a novel easy method for obtaining 3-carboxy-4-(i?)- phenylpyrrolidine-2-one from the racemate, by using a new resolution reagent in industrially applicable solvent.
The current invention is illustrated by the following non-limiting examples.
Examples
Following examples are not deemed to limit the invention in any way and are used for demonstration purposes only.
Example 1. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one salt with 3 -(^-benzoyl oxyquinuclidine.
3-Carboxy-4-(i?,5)-phenylpyrrolidine-2-one (210 g) was suspended in ethanol (570 ml). The suspension was heated to approx. 60 °C and 3-(5)-benzoyloxyquinuclidine (240 g) solution in
ethanol (240 ml) was added upon stirring. The reaction mixture was stirred at this temperature for approx. 20 min and then was allowed to cool down to room temperature. Crystalline precipitate was filtered off and washed with ethanol (300 ml). The obtained salt was dried, then dissolved in hot water (750 ml), filtered and allowed to crystallize at room temperature for 2 h. Crystalline precipitate was filtered off, washed with water (200 ml) and dried. The yield was 160 g of a white crystalline salt. [a]D 20 (methanol, c = 2) = -55.7°; melting temp. 170-172 °C (decomp.).; C25H28N2O5, calc. %: C 68.79; H 6.47; N 6.42, found %: C 68.94; H 6.46; N 6.42.
Example 2. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one salt with 3 -(^-benzoyl oxyquinuclidine.
3-Carboxy-4-(i?,5)-phenylpyrrolidine-2-one (210 g) was suspended in acetonitrile (520 ml). The suspension was heated to approx. 60 °C and 3-(5)-benzoyloxyquinuclidine (240 g) solution in acetonitrile (320 ml) was added upon stirring. The reaction mixture was stirred at this temperature for approx. 20 min and then was allowed to cool down to room temperature.
Crystalline precipitate was filtered off and washed with acetonitrile (170 ml). The obtained salt was dried, then dissolved in hot water (750 ml), filtered and allowed to crystallize at room temperature for 2 h. Crystalline precipitate was filtered off, washed with water (200 ml) and dried. The yield was 152 g of a white crystalline salt. [α]ϋ20 (methanol, c = 2) = -56.2°; melting temp. 170-172 °C (decomposition).
Example 3. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one.
3-Carboxy-4-(i?)-phenylpyrrolidine-2-one salt with 3-(<S -benzoyloxyquinuclidine (160 g) was dissolved in water (700 ml) at 65 °C and concentrated HC1 (40 ml) was added dropwise until pH <3. Precipitation of white crystals of 3-carboxy-4-(i?)-phenylpyrrolidine-2-one was observed. Reaction mixture was cooled down to room temperature. After 2 h standing at the room temperature the precipitate was filtered off, washed with water (200 ml) at room temperature and dried in vacuum. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one (70 g) was obtained as white crystalline solid (yield from racemate 34.3%), melting temp. 136.5 °C,
(methanol, c = 2) = -138.6°.
Claims
Claims
1. 3-Carboxy-4-(i?)-phenylpyrrolidine-2-one salt with 3 -(^-benzoyl oxyquinuclidine (I)
(I)
A method for obtaining 3-carboxy-4-(i?)-phenylpyrrolidine-2-one, characterized in that 3-carboxy-4-(i?,5)-phenylpyrrolidine-2-one is reacted with 3-(<S)- benzoyloxyquinuclidine in a solvent, followed by isolation of the obtained salt (I), purification and treatment with a mineral acid.
The method according to claim 2, wherein the solvent is selected from a group, comprising water, methanol, ethanol, propanol-1, propanol-2, acetonitrile and mixtures thereof.
4. The method according to claim 2, wherein the solvent is ethanol.
5. The method according to claim 2, wherein the solvent is acetonitrile.
6. The method according to claim 2, wherein the salt (I) purification is performed by crystallization from water.
The method according to claim 2, wherein the mineral acid is hydrochloric acid.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA201691190A EA027373B1 (en) | 2013-12-13 | 2014-12-12 | Method for separating racemic 3-carboxy-4-phenylpyrrolydine-2-one using 3-(s)-benzoyloxyquinuclidine |
| UAA201606170A UA114161C2 (en) | 2013-12-13 | 2014-12-12 | 3-CARBOXY-4- (R)-PHENYLPYROLIDINE-2-SALT SALT AND ITS USE |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-13-209A LV15015B (en) | 2013-12-13 | 2013-12-13 | Salt of 3-carboxy-4-(r)-phenylpyrrolidinone-2 and uses thereof |
| LVP-13-209 | 2013-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2015087291A1 true WO2015087291A1 (en) | 2015-06-18 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2014/066846 WO2015087291A1 (en) | 2013-12-13 | 2014-12-12 | 3-carboxy-4-(r)-phenylpyrrolydine-2-one salt and its use |
Country Status (4)
| Country | Link |
|---|---|
| EA (1) | EA027373B1 (en) |
| LV (1) | LV15015B (en) |
| UA (1) | UA114161C2 (en) |
| WO (1) | WO2015087291A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007104780A2 (en) | 2006-03-16 | 2007-09-20 | Akciju Sabiedriba 'olainfarm' | N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use |
| LV13635B (en) | 2006-02-23 | 2008-01-20 | Olainfarm As | Enzymatic resolution of racemic 3-aryl-4-aminobutyric acids |
-
2013
- 2013-12-13 LV LVP-13-209A patent/LV15015B/en unknown
-
2014
- 2014-12-12 UA UAA201606170A patent/UA114161C2/en unknown
- 2014-12-12 EA EA201691190A patent/EA027373B1/en unknown
- 2014-12-12 WO PCT/IB2014/066846 patent/WO2015087291A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LV13635B (en) | 2006-02-23 | 2008-01-20 | Olainfarm As | Enzymatic resolution of racemic 3-aryl-4-aminobutyric acids |
| WO2007104780A2 (en) | 2006-03-16 | 2007-09-20 | Akciju Sabiedriba 'olainfarm' | N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use |
Non-Patent Citations (5)
| Title |
|---|
| BIOORG. &MED. CHEM. LETT., vol. 14, pages 3781 - 3784 |
| ELIEL E L ET AL: "CHEMICAL SEPARATION OF ENANTIOMERS VIA DIASTEREOMERS", STEREOCHEMISTRY OF ORGANIC COMPOUNDS, XX, XX, 1 January 1994 (1994-01-01), pages 322 - 336, XP002459712 * |
| POL. J. CHEM., vol. 53, 1979, pages 435 - 446 |
| SOBOCINSKA, MARIA; ZOBACHEVA, MAIA M.; PEREKALIN, VSEVOLOD V.; KUPRYSZEWSKI, GOTFRYD: "Configuration of 4-aryl-2-pyrrolidinones and their 3-carboxy derivatives", POLISH JOURNAL OF CHEMISTRY, vol. 53, 1979, pages 435 - 446, XP002737419 * |
| SYNTHESIS, 1991, pages 1023 - 1026 |
Also Published As
| Publication number | Publication date |
|---|---|
| UA114161C2 (en) | 2017-04-25 |
| LV15015B (en) | 2015-12-20 |
| LV15015A (en) | 2015-06-20 |
| EA201691190A1 (en) | 2016-12-30 |
| EA027373B1 (en) | 2017-07-31 |
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