CA1097357A - Preparation of isotopically labelled aminopyrine - Google Patents
Preparation of isotopically labelled aminopyrineInfo
- Publication number
- CA1097357A CA1097357A CA293,632A CA293632A CA1097357A CA 1097357 A CA1097357 A CA 1097357A CA 293632 A CA293632 A CA 293632A CA 1097357 A CA1097357 A CA 1097357A
- Authority
- CA
- Canada
- Prior art keywords
- aminopyrine
- isotopically labelled
- preparation
- labelled
- amines
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 title abstract description 5
- 229960000212 aminophenazone Drugs 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N 4-aminoantipyrine Chemical compound CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 abstract description 9
- 229910000043 hydrogen iodide Inorganic materials 0.000 abstract description 8
- 150000001412 amines Chemical class 0.000 abstract description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract description 5
- 230000029936 alkylation Effects 0.000 abstract description 4
- 238000005804 alkylation reaction Methods 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 238000007449 liver function test Methods 0.000 abstract 1
- 239000011368 organic material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical group [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
TITLE OF THE INVENTION
Preparation of Isotopically Labelled Aminopyrine ABSTRACT OF THE DISCLOSURE
The present invention relates to preparation of isotopically labelled amines by alkylation with isotopic-ally labelled methyl iodide in the presence of an organic material capable of reaction with the formed hydrogen iodide. Such methylated amines, particularly isotopically labelled aminopyrine, are useful as clinical diagnostic aids in liver function tests.
Preparation of Isotopically Labelled Aminopyrine ABSTRACT OF THE DISCLOSURE
The present invention relates to preparation of isotopically labelled amines by alkylation with isotopic-ally labelled methyl iodide in the presence of an organic material capable of reaction with the formed hydrogen iodide. Such methylated amines, particularly isotopically labelled aminopyrine, are useful as clinical diagnostic aids in liver function tests.
Description
7~
11 BAC~GROUND OF THE INVENTION
-12 One method useful for the preparation of iso-13 topically labelled amines is alkylation of a primary amine 14 using isotopically labelled methyl iodide. Prior art processes ordinarily carry out such alkylations in the 16 presence of aprotic solvents such as dioxane or benzene 17 with concurrent production of hydrogen iodide.
18 In other instances, these alkylations are car-19 ried out in the presence of base which is added to the reaction mixture in order to remove the hydrogen iodide 21 as it is formed. In the case of acid or base sensitive 22 amines, either of the above procedures may result in the 23 destruction o either starting material or final product 24 with a resultant impure product or lowered yield.
DETAILS OF THE IN~ENTION
26 In accordance with the present invention, iso-27 topically labelled tertiary amines such as aminopyrine 1513g 1 are prepared from the corresponding primary amine by
11 BAC~GROUND OF THE INVENTION
-12 One method useful for the preparation of iso-13 topically labelled amines is alkylation of a primary amine 14 using isotopically labelled methyl iodide. Prior art processes ordinarily carry out such alkylations in the 16 presence of aprotic solvents such as dioxane or benzene 17 with concurrent production of hydrogen iodide.
18 In other instances, these alkylations are car-19 ried out in the presence of base which is added to the reaction mixture in order to remove the hydrogen iodide 21 as it is formed. In the case of acid or base sensitive 22 amines, either of the above procedures may result in the 23 destruction o either starting material or final product 24 with a resultant impure product or lowered yield.
DETAILS OF THE IN~ENTION
26 In accordance with the present invention, iso-27 topically labelled tertiary amines such as aminopyrine 1513g 1 are prepared from the corresponding primary amine by
2 methylation using isotopically labelled methyl iodide.
3 In order to protect the acid sensitive amines such as
4 aminopyrine, a substance capable of reaction with the formed hydrogen iodide is added to the reaction mixture 6 preferably as a solvent or liquid diluent for the reac-7 tion.
8 The hydrogen iodide acceptor employed in the 9 process of the invention is a lower alcohol of from 3-10 carbon atoms or an unsaturated ether of from 3-10 carbon 11 atoms.
12 This hydrogen iodide acceptor material is em-13 ployed in at least an equimolar ratio to the methyl iodide 14 employed, but it is possible to use an excess of the alcohol or ether as solvent for the reaction if required 16 by the solubility of the reactants. Preferably, approxi-17 mately an equimolar amount of methyl iodide and a lower 18 alcohol of from 3-10 carbon atoms is employed. In this 19 preferred method of operation, the fonmed hydrogen iodide reacts with the alcohol present, forming the corresponding 21 alkyl iodide or an isomer thereof, and it forms a separate 22 layer in ~he reaction mixture which is readily separated 23 from the isotopically labelled amine.
24 After separation of the isotopically labelled methylated amine, it is readily purified by recrystalli-26 zation from a lower alcohol as the hydrogen iodide addition 27 salt.
3~
1 ExAMæLE 1 2 N-~lethylation of 4-Amino-2,3-dimethyl-1-phenyl-3-pyrazolin-3 5-one (4-aminoantipy~ine) with (13C)-iodomethane in 1-4 propanol to give 4-(13C2)-dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one S 4-Amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one 7 (50 g., 0.123 mole), l-propanol (50 ml.), and (13C)-iodo-8 methane (75 g., 33 ml., 0.25 mole) are placed in a pressure 9 bottle and heated on a boiling water bath for 24 hours.
The upper phase consistin~ of 2-iodopropane is discarded.
11 The lower phase is diluted to twice its volume with 1-12 propanol. ~rystallization of 4 (13C2)-dimethyl-ammonium-13 2,3 dimethyl-1-phenyl-3-pyrazvlin-5-one iodide is allowed 14 to proceed. This salt is filtered off and washed with cold l-propanol until the washings are colorless. The 16 solid is suspended in ethanol (500 ml.) and a cold satu-17 rated solution of anhydrous potassium carbonate (50 g.) 18 in water is added and the mixture stirred until all solid 19 has gone into solution. The lower layer is discarded.
The residue obtained upon evaporation of the upper layer 21 is recrystallized twice from hot 2-propyl ether. Yield 22 27 g. (47%). The product is pure.
~,
8 The hydrogen iodide acceptor employed in the 9 process of the invention is a lower alcohol of from 3-10 carbon atoms or an unsaturated ether of from 3-10 carbon 11 atoms.
12 This hydrogen iodide acceptor material is em-13 ployed in at least an equimolar ratio to the methyl iodide 14 employed, but it is possible to use an excess of the alcohol or ether as solvent for the reaction if required 16 by the solubility of the reactants. Preferably, approxi-17 mately an equimolar amount of methyl iodide and a lower 18 alcohol of from 3-10 carbon atoms is employed. In this 19 preferred method of operation, the fonmed hydrogen iodide reacts with the alcohol present, forming the corresponding 21 alkyl iodide or an isomer thereof, and it forms a separate 22 layer in ~he reaction mixture which is readily separated 23 from the isotopically labelled amine.
24 After separation of the isotopically labelled methylated amine, it is readily purified by recrystalli-26 zation from a lower alcohol as the hydrogen iodide addition 27 salt.
3~
1 ExAMæLE 1 2 N-~lethylation of 4-Amino-2,3-dimethyl-1-phenyl-3-pyrazolin-3 5-one (4-aminoantipy~ine) with (13C)-iodomethane in 1-4 propanol to give 4-(13C2)-dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one S 4-Amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one 7 (50 g., 0.123 mole), l-propanol (50 ml.), and (13C)-iodo-8 methane (75 g., 33 ml., 0.25 mole) are placed in a pressure 9 bottle and heated on a boiling water bath for 24 hours.
The upper phase consistin~ of 2-iodopropane is discarded.
11 The lower phase is diluted to twice its volume with 1-12 propanol. ~rystallization of 4 (13C2)-dimethyl-ammonium-13 2,3 dimethyl-1-phenyl-3-pyrazvlin-5-one iodide is allowed 14 to proceed. This salt is filtered off and washed with cold l-propanol until the washings are colorless. The 16 solid is suspended in ethanol (500 ml.) and a cold satu-17 rated solution of anhydrous potassium carbonate (50 g.) 18 in water is added and the mixture stirred until all solid 19 has gone into solution. The lower layer is discarded.
The residue obtained upon evaporation of the upper layer 21 is recrystallized twice from hot 2-propyl ether. Yield 22 27 g. (47%). The product is pure.
~,
Claims
1. Process for the preparation of 4-(13C2)-dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one which comprises reacting 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with (13C)-iodomethane in the presence of 1-propanol and isolating the desired compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA293,632A CA1097357A (en) | 1977-12-21 | 1977-12-21 | Preparation of isotopically labelled aminopyrine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA293,632A CA1097357A (en) | 1977-12-21 | 1977-12-21 | Preparation of isotopically labelled aminopyrine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097357A true CA1097357A (en) | 1981-03-10 |
Family
ID=4110353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA293,632A Expired CA1097357A (en) | 1977-12-21 | 1977-12-21 | Preparation of isotopically labelled aminopyrine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1097357A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478509A (en) * | 2016-09-28 | 2017-03-08 | 中国农业科学院植物保护研究所 | The synthetic method of the aminopyrine that a kind of carbon 13 is marked |
-
1977
- 1977-12-21 CA CA293,632A patent/CA1097357A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478509A (en) * | 2016-09-28 | 2017-03-08 | 中国农业科学院植物保护研究所 | The synthetic method of the aminopyrine that a kind of carbon 13 is marked |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |