CA1059137A - Process for the preparation of therapeutically valuable 2-oxo-1-pyrrolidinylacetamide - Google Patents
Process for the preparation of therapeutically valuable 2-oxo-1-pyrrolidinylacetamideInfo
- Publication number
- CA1059137A CA1059137A CA247,190A CA247190A CA1059137A CA 1059137 A CA1059137 A CA 1059137A CA 247190 A CA247190 A CA 247190A CA 1059137 A CA1059137 A CA 1059137A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- preparation
- compound
- organic solvent
- oxo
- 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.)
- Expired
Links
Classifications
-
- 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
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
Abstract
ABSTRACT OF THE DISCLOSURE
An improved process is provided for the preparation of piracetam (2-oxo-1-pyrrilidinylacetamide) involving a ring colsure reaction on N-carbamoylmethyl-4-aminobutryric acid ethyl ester being the simple expedient of heating. This procedure obviates the use of dangerous raw materials.
An improved process is provided for the preparation of piracetam (2-oxo-1-pyrrilidinylacetamide) involving a ring colsure reaction on N-carbamoylmethyl-4-aminobutryric acid ethyl ester being the simple expedient of heating. This procedure obviates the use of dangerous raw materials.
Description
m is invention relates to a new p~ocess for the preparation of
2-oxo-1-pyrrilidinylacetamide or piracetam, namely a compound having the formula ~, .
CH2-C0-NH2 , and to the intermediates used to produce such compound.
Piracetam is a so-called cerebrotonicum, which is used for in- -stance in travel sickness and the therapy of locomotorial diseases, hyper-tension and epilepsy. It is widely used also in geriatry for improving cerebral activity. m e use of piracetam is thus very wide and the toxicity is 1c~7.
The preparation of piracetam has previously been described, e.g.
in U.S. Patent No. 3,459,738 issued Aug. 5, 1969 to Henri ~orren, Forest, Belgium, assign~r to UCB (Union Chimique-Chemische Eedrijven), Saint-Gilles-Br~ssels, Belgium, wherein it is prepared either from the correspond- t ing ester and ammonia or by reacting a metal salt of 2-oxo-pyrrolidine ~7ith r chloroacetamide.
In the above identified U.S. Patent, the procedure commences either from the alk~li metal salt of 2-ox~pyrrolidine or from 2-oxo-1-pyrrolidinyl-acetic acid ester, which is prepared from the above mentioned aIkali salt and chloroacetic acid ester. In the preparation of the sodium salt of 2-oxopyrrolidine, either metallic sodium or sodium amide are used, and in the synthesis of the amide from the ester, gaseous ammDnia is used. m us, the process of the above identified U.S. Patent involves the use of danger-ous raw 7naterials.
It would therefore be desirable to provide a process for the preparation of piracetam which does not inv~lve the use of dangerous raw material~. According to a broad aspect of the present invention, the ~uç--et n is prepared by ring closure reaction. By one variant, glycina-i7, ~' ,.~
. ' ' ~059137 mide hydrochloride is first reacted with 4-chlorobutyric acid ethyl ester formung N-carbamoyLmet hyl-4-aminoputyric acid ethyl ester, which is a new compound, which is then cvclized to piracetam by heating.
Thus, by~ a broad aspect of this invention an inçrovement is pro-vided in a process for the preparation of piracetam (2-oxo-1-pyrrolidinyl-acetamide), a therapeutically valuahle compound of the formula N -Cil2 -CO-NH2 the step which comprises heating an amino acid ester of the form~la ~I ~ `, \ CH2-CH2-CH2{0CC2H5, thereby to split off ethanol and to cyclize the amino acid ester.
By one variant, the heating is at a temperature of 1~0 - 180C.
By anoth.er aspect, a process is provided for the preparation of 2-oxo-1-pyrrolidinylacetamide, a therapeutically valuable oompound of the formula ~0 ~,, which oomprises: boiling glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester together in an organic solvent in the presence of an acid binding agent and a catalytic amount of potasslum iodide, thereby to form an amino acid ester of the formula , S, . .
~, :, , , ': , . ~, . . - , ,. . ;
' ;' ., ~ ' :' . . . , :, :. -., : :
~`` 1059137 `
CH2-CH2-CH2-CC2H5;
and then heating the can?ound to a temperature of 160 - 180C, thereby to split off ethanol and to cyclize the am mo acid ester.
By one variant, the organic solvent is an alcohol and the acid binding agent is sodium carbonate.
By a variation thereof, the process includes the step of simul-taneously distilling off split-off ethanol as it is formed.
In another aspect of the invention the N-carbamoylmethyl-4-amino-butyric acid ethyl ester is prepared by reacting glycinamide hydrochloride with 4-chlorobutyric acid. r By a variant thereof, the reaction is carried out by boiling glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester in an organic solvent in the presence of an acid binding agent and a catalytic amount of potassium iodide.
- By a variation thereof, the organic solvent is alcohol, and the acid binding agent is sodium carbonate. r m e N-carbamoylmethyl-4-amino butyric acid ethyl ester is a new con~ound providing another aspect of this invention.
From textbooks in chemistry (e.g. Houben-hTeyl: Methoden der organischen Chemie, Stickstoffverbindungen II/III, Georg Thieme Verlag, Stuttgart 1958, p. 529), it is known that amino acids, their esters, amides and nitriles can be cyclized to lactames. Hcwever, the reactions of N-substituted amino acids have not been studied much. m e process of a broad aspect of this invention is thus to be considered a new ~7ay to sol~e the ~ piracetam synthesis. m e reaction scheme of the process of an aspect of ; this invention is the folla~7ing:
.. ...
` ~ 1059137 H2N-CH2-CO-~H2.HCl~Cl- OE 2-CH2-CH2 ~00C2H5 ,, CH -CO-NH ' Na2C3 ~ N~ heating >
CH2-CH2-CH2-CO~c2H5 (I) ~
r I _L O +C2H5H
'Nr C1~2-CO-NH2 me intermediate I is a new oompound, which has not earlier been described in the literature. Glycinamide hydrochloride and 4-chiorobutyric acid ethyl ester are industrial raw materials. The reaction between them is simple: the agents are boiled in an organic solvent, preferably an alcohol, e.g. ethanol, in the presence of an equivalent am~unt of sodium carbonate and a catalytic amount of potassium iodide. The formed inter- ~
mediate I can be heated to a temperature of 160 - 180C, without isolation t of the pure product, which leads to ring closure. m e process is conse-20 quently simple in its entirety and the yield is good.
The prncess of broad aspects of the invention has, when oompared to the above identified U.S. Patent, the advantage that no dangerous raw ~ -materials being used. m e process according to aspects of this invention can therefore be carried out with remarkably simpler equipment.
The invention is illustrated by the following exa~ple:
Example 1 22.1 g of glycinamide hydrochloride, 30.1 g of 4-chlorobutyric -acid ethyl ester, 21.2 g of sodium carbonate and 0.5 g of potassium iodide i are refluxed in 100 ml of ethanol. ~hen the reaction is oompleted after ~h ~ - 3 a -, .
':. , '' ' , : ' ' ' , ' : ''','., . '": .''~,,.~'," ' ' '',, ' , , . . . .
~ 1059137 16 hours, the suspension is filtered and the ethanol is distilled off.
m e residue, 34.2 g (9. per cent), is composed of crude N-carb~mDylmethyl-4-aminobutyric acid ethyl ester. This is a solid agent having a melting point of 100 - 115C, but it has never been obtained in a quite pure state r as it always contains small am~unts of piracetam.
The residue can be used in the foll~^~ing step without isolation.
It is heated to 170C. and the formed ethanol is distilled off. m e heating is oontinued so long as ethanol distils over, then is cooled and crystallized r from isopropanol. Yield 21.7 g of piracetam (total yield 76.4%). The melting point is 150 - 152C. t ~, ,.
: ~ - 3 b -
CH2-C0-NH2 , and to the intermediates used to produce such compound.
Piracetam is a so-called cerebrotonicum, which is used for in- -stance in travel sickness and the therapy of locomotorial diseases, hyper-tension and epilepsy. It is widely used also in geriatry for improving cerebral activity. m e use of piracetam is thus very wide and the toxicity is 1c~7.
The preparation of piracetam has previously been described, e.g.
in U.S. Patent No. 3,459,738 issued Aug. 5, 1969 to Henri ~orren, Forest, Belgium, assign~r to UCB (Union Chimique-Chemische Eedrijven), Saint-Gilles-Br~ssels, Belgium, wherein it is prepared either from the correspond- t ing ester and ammonia or by reacting a metal salt of 2-oxo-pyrrolidine ~7ith r chloroacetamide.
In the above identified U.S. Patent, the procedure commences either from the alk~li metal salt of 2-ox~pyrrolidine or from 2-oxo-1-pyrrolidinyl-acetic acid ester, which is prepared from the above mentioned aIkali salt and chloroacetic acid ester. In the preparation of the sodium salt of 2-oxopyrrolidine, either metallic sodium or sodium amide are used, and in the synthesis of the amide from the ester, gaseous ammDnia is used. m us, the process of the above identified U.S. Patent involves the use of danger-ous raw 7naterials.
It would therefore be desirable to provide a process for the preparation of piracetam which does not inv~lve the use of dangerous raw material~. According to a broad aspect of the present invention, the ~uç--et n is prepared by ring closure reaction. By one variant, glycina-i7, ~' ,.~
. ' ' ~059137 mide hydrochloride is first reacted with 4-chlorobutyric acid ethyl ester formung N-carbamoyLmet hyl-4-aminoputyric acid ethyl ester, which is a new compound, which is then cvclized to piracetam by heating.
Thus, by~ a broad aspect of this invention an inçrovement is pro-vided in a process for the preparation of piracetam (2-oxo-1-pyrrolidinyl-acetamide), a therapeutically valuahle compound of the formula N -Cil2 -CO-NH2 the step which comprises heating an amino acid ester of the form~la ~I ~ `, \ CH2-CH2-CH2{0CC2H5, thereby to split off ethanol and to cyclize the amino acid ester.
By one variant, the heating is at a temperature of 1~0 - 180C.
By anoth.er aspect, a process is provided for the preparation of 2-oxo-1-pyrrolidinylacetamide, a therapeutically valuable oompound of the formula ~0 ~,, which oomprises: boiling glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester together in an organic solvent in the presence of an acid binding agent and a catalytic amount of potasslum iodide, thereby to form an amino acid ester of the formula , S, . .
~, :, , , ': , . ~, . . - , ,. . ;
' ;' ., ~ ' :' . . . , :, :. -., : :
~`` 1059137 `
CH2-CH2-CH2-CC2H5;
and then heating the can?ound to a temperature of 160 - 180C, thereby to split off ethanol and to cyclize the am mo acid ester.
By one variant, the organic solvent is an alcohol and the acid binding agent is sodium carbonate.
By a variation thereof, the process includes the step of simul-taneously distilling off split-off ethanol as it is formed.
In another aspect of the invention the N-carbamoylmethyl-4-amino-butyric acid ethyl ester is prepared by reacting glycinamide hydrochloride with 4-chlorobutyric acid. r By a variant thereof, the reaction is carried out by boiling glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester in an organic solvent in the presence of an acid binding agent and a catalytic amount of potassium iodide.
- By a variation thereof, the organic solvent is alcohol, and the acid binding agent is sodium carbonate. r m e N-carbamoylmethyl-4-amino butyric acid ethyl ester is a new con~ound providing another aspect of this invention.
From textbooks in chemistry (e.g. Houben-hTeyl: Methoden der organischen Chemie, Stickstoffverbindungen II/III, Georg Thieme Verlag, Stuttgart 1958, p. 529), it is known that amino acids, their esters, amides and nitriles can be cyclized to lactames. Hcwever, the reactions of N-substituted amino acids have not been studied much. m e process of a broad aspect of this invention is thus to be considered a new ~7ay to sol~e the ~ piracetam synthesis. m e reaction scheme of the process of an aspect of ; this invention is the folla~7ing:
.. ...
` ~ 1059137 H2N-CH2-CO-~H2.HCl~Cl- OE 2-CH2-CH2 ~00C2H5 ,, CH -CO-NH ' Na2C3 ~ N~ heating >
CH2-CH2-CH2-CO~c2H5 (I) ~
r I _L O +C2H5H
'Nr C1~2-CO-NH2 me intermediate I is a new oompound, which has not earlier been described in the literature. Glycinamide hydrochloride and 4-chiorobutyric acid ethyl ester are industrial raw materials. The reaction between them is simple: the agents are boiled in an organic solvent, preferably an alcohol, e.g. ethanol, in the presence of an equivalent am~unt of sodium carbonate and a catalytic amount of potassium iodide. The formed inter- ~
mediate I can be heated to a temperature of 160 - 180C, without isolation t of the pure product, which leads to ring closure. m e process is conse-20 quently simple in its entirety and the yield is good.
The prncess of broad aspects of the invention has, when oompared to the above identified U.S. Patent, the advantage that no dangerous raw ~ -materials being used. m e process according to aspects of this invention can therefore be carried out with remarkably simpler equipment.
The invention is illustrated by the following exa~ple:
Example 1 22.1 g of glycinamide hydrochloride, 30.1 g of 4-chlorobutyric -acid ethyl ester, 21.2 g of sodium carbonate and 0.5 g of potassium iodide i are refluxed in 100 ml of ethanol. ~hen the reaction is oompleted after ~h ~ - 3 a -, .
':. , '' ' , : ' ' ' , ' : ''','., . '": .''~,,.~'," ' ' '',, ' , , . . . .
~ 1059137 16 hours, the suspension is filtered and the ethanol is distilled off.
m e residue, 34.2 g (9. per cent), is composed of crude N-carb~mDylmethyl-4-aminobutyric acid ethyl ester. This is a solid agent having a melting point of 100 - 115C, but it has never been obtained in a quite pure state r as it always contains small am~unts of piracetam.
The residue can be used in the foll~^~ing step without isolation.
It is heated to 170C. and the formed ethanol is distilled off. m e heating is oontinued so long as ethanol distils over, then is cooled and crystallized r from isopropanol. Yield 21.7 g of piracetam (total yield 76.4%). The melting point is 150 - 152C. t ~, ,.
: ~ - 3 b -
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. In a process for the preparation of 2-oxo-1-pyrrolidinylace-tamide, a therapeutically valuable compound of the formula the step which comprises heating an amino acid ester of the formula thereby to split off ethanol and to cyclize said amino acid ester.
2. The process of claim 1 wherein the heating is at a temperature of 160 - 180°C.
3. A process for the preparation of 2-oxo-pyrrolidinylacetamide, a therapeutically valuable compound of the formula which comprises: boiling glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester together in an organic solvent in the presence of an acid bind-ing agent and a catalytic amount of potassium iodide, thereby to form an amino acid ester of the formula and then heating said compound to a temperature of 160 - 180°C., thereby to split off ethanol and to cyclize said amino acid ester.
4. The process of claim 3 wherein the organic solvent is an al-cohol and the acid binding agent is sodium carbonate.
5. The process of claims 3 or 4 including the step of simutane-ously distilling off split-off ethanol as it is formed.
6. In the process for the preparation of a therapeutically valua-ble compound of the formula the improvement which comprises preliminary step of forming formula by reacting glycinamide hydrochloride with 4-chlorobutyric acid ethyl ester.
7. The process of claim 6 wherein said reaction is carried out by boiling glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester in an organic solvent in the presence of an acid binding agent and a catalytic amount of potassium iodide.
8. The process of claim 7 wherein the organic solvent is alcohol, and the acid binding agent is sodium carbonate.
9. The compound whenever prepared by the-process of claims 6, 7 or 8 or by their obvious chemical equivalents.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI750944A FI51098C (en) | 1975-03-27 | 1975-03-27 | Process for the preparation of therapeutically valuable 2-oxo-1-pyrrolidinylacetamide. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1059137A true CA1059137A (en) | 1979-07-24 |
Family
ID=8509097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA247,190A Expired CA1059137A (en) | 1975-03-27 | 1976-03-05 | Process for the preparation of therapeutically valuable 2-oxo-1-pyrrolidinylacetamide |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS51113867A (en) |
| AT (1) | AT347447B (en) |
| CA (1) | CA1059137A (en) |
| CH (1) | CH599151A5 (en) |
| ES (1) | ES445762A1 (en) |
| FI (1) | FI51098C (en) |
| NL (1) | NL7602263A (en) |
| PT (1) | PT64933B (en) |
| SU (1) | SU655304A3 (en) |
| YU (1) | YU45476A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223328A1 (en) | 1985-07-26 | 1987-05-27 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| US4797496A (en) * | 1984-02-27 | 1989-01-10 | I.S.F. Societa Per Azioni | Process for the preparation of pyrrolidone derivatives |
| WO2011049475A1 (en) | 2009-10-23 | 2011-04-28 | Uniwersytet Jagielloński | The new application of 2-pyrrolidone derivatives |
| RU2629117C1 (en) * | 2016-06-14 | 2017-08-24 | Сизов Владимир Владимирович | Method of producing 4-substituted 2-[2-oxo-1-pyrrolidinyl] acetamide |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT391134B (en) * | 1979-03-22 | 1990-08-27 | Continental Pharma | Process for the preparation of novel glycinamide derivatives, their addition salts and their optical isomers |
| CH680293A5 (en) * | 1990-06-26 | 1992-07-31 | Lonza Ag | |
| JP2969616B2 (en) * | 1994-11-24 | 1999-11-02 | 田辺製薬株式会社 | Method for producing 4-mercaptopyrrolidine compound |
-
1975
- 1975-03-27 FI FI750944A patent/FI51098C/en not_active IP Right Cessation
-
1976
- 1976-02-21 JP JP1838876A patent/JPS51113867A/en active Granted
- 1976-02-24 YU YU45476A patent/YU45476A/en unknown
- 1976-03-04 ES ES445762A patent/ES445762A1/en not_active Expired
- 1976-03-04 NL NL7602263A patent/NL7602263A/en not_active Application Discontinuation
- 1976-03-05 CA CA247,190A patent/CA1059137A/en not_active Expired
- 1976-03-22 PT PT6493376A patent/PT64933B/en unknown
- 1976-03-23 CH CH361876A patent/CH599151A5/en not_active IP Right Cessation
- 1976-03-26 AT AT223576A patent/AT347447B/en not_active IP Right Cessation
-
1977
- 1977-12-05 SU SU772549949A patent/SU655304A3/en active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4797496A (en) * | 1984-02-27 | 1989-01-10 | I.S.F. Societa Per Azioni | Process for the preparation of pyrrolidone derivatives |
| EP0223328A1 (en) | 1985-07-26 | 1987-05-27 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| EP0223328B1 (en) * | 1985-07-26 | 1992-01-29 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| WO2011049475A1 (en) | 2009-10-23 | 2011-04-28 | Uniwersytet Jagielloński | The new application of 2-pyrrolidone derivatives |
| RU2629117C1 (en) * | 2016-06-14 | 2017-08-24 | Сизов Владимир Владимирович | Method of producing 4-substituted 2-[2-oxo-1-pyrrolidinyl] acetamide |
Also Published As
| Publication number | Publication date |
|---|---|
| PT64933A (en) | 1976-04-01 |
| CH599151A5 (en) | 1978-05-12 |
| NL7602263A (en) | 1976-09-29 |
| AT347447B (en) | 1978-12-27 |
| SU655304A3 (en) | 1979-03-30 |
| FI51098B (en) | 1976-06-30 |
| JPS51113867A (en) | 1976-10-07 |
| YU45476A (en) | 1982-05-31 |
| PT64933B (en) | 1977-08-24 |
| ATA223576A (en) | 1978-05-15 |
| FI51098C (en) | 1976-10-11 |
| ES445762A1 (en) | 1977-06-01 |
| JPS5652017B2 (en) | 1981-12-09 |
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