CN106478509A - The synthetic method of the aminopyrine that a kind of carbon 13 is marked - Google Patents
The synthetic method of the aminopyrine that a kind of carbon 13 is marked Download PDFInfo
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- CN106478509A CN106478509A CN201610862851.6A CN201610862851A CN106478509A CN 106478509 A CN106478509 A CN 106478509A CN 201610862851 A CN201610862851 A CN 201610862851A CN 106478509 A CN106478509 A CN 106478509A
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- synthetic method
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- formic acid
- paraformaldehyde
- aminopyrine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
- C07D231/48—Oxygen atom in position 3 or 5 and nitrogen atom in position 4 with hydrocarbon radicals attached to said nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of synthetic method of the aminopyrine of the mark of carbon 13, comprises the following steps：(1) by 4 amino-antipyrines and formic acid, heating response in reaction vessel obtains liquid I；(2) formaldehyde is added in the liquid I obtained to step (1)13C or paraformaldehyde13C, continues to react to obtain liquid II；(3) the liquid II for obtaining step (2) is neutralized with alkali, then is extracted with organic solvent, and precipitation obtains solid I；(4) the solid I solvent recrystallization for obtaining step (3), activated carbon decolorizing, finally give target product.Product structure is characterized by high resolution mass spectrum, Pyrolysis Mass Spectrometry, nucleus magnetic hydrogen spectrum, carbon spectrum and infrared spectrum etc., it was demonstrated that product is the aminopyrine that carbon 13 is marked.Qualitative analysis shows that the synthetic method can obtain chemical purity and reach more than 99%, the product of stable isotope abundance more than 99%.
Description
Technical field
The invention belongs to stable isotope labelled compound synthesis technical field, and in particular to a kind of ammonia of labeling
The synthetic method of Ji Bilin.
Background technology
The breathing reagent that carbon stable isotope -13 is marked, due to safe, easy, noninvasive, sensitivity and high specificity
The features such as gradually instead of radioreagent, play a greater and greater role in clinical medical medical diagnosis on disease.Aminopyrine
The features such as breath test has safe and simple and reproducible, can reflect in microsomal mixed function oxidase system exactly
The function of P450, is chronic liver disease classification, the important criterion of assessment.Therefore, the conjunction of the aminopyrine reagent of labeling
The medical fast and safely detection hepatopathy of Cheng Kewei and hepatopathy grading, provide basic agent.
Content of the invention
It is an object of the invention to provide a kind of synthetic method of the aminopyrine of labeling.
The purpose of the present invention is achieved through the following technical solutions：
A kind of synthetic method of the aminopyrine of labeling, comprises the following steps：
(1) 4-AA and formic acid are added in reaction vessel, heating response obtains liquid I；
(2) in the liquid I obtained to step (1) add formaldehyde-13C or paraformaldehyde-13C, continues to react to obtain liquid II；
(3) the liquid II for obtaining step (2) is neutralized with alkali, then obtains solid I with organic solvent extraction, precipitation；
(4) the solid I solvent recrystallization that step (3) is obtained, activated carbon decolorizing, final product.
Further, the 4-AA, formic acid and formaldehyde in described step (1) and (2)-13C or paraformaldehyde-13C
For the aqueous solution or solid reagent, the mol ratio 4-AA of three, formic acid and formaldehyde-13C is 1:3～5:2～3 or 4-
Amino-antipyrine, formic acid and paraformaldehyde-13C is 1:3～5:0.67～1, and the solvent used by three is water or organic molten
Agent.
Further, in described step (1) and (2), reaction temperature is 40～150 DEG C.
Further, in described step (1) and (2), the reaction time is respectively 1～12 hour.
Further, in described step (3), alkali used is inorganic base or organic base.Organic solvent used include just oneself
Alkane, ether, petroleum ether, ethyl acetate, benzene,toluene,xylene, dichloromethane, chloroform or tetrachloromethane.
Further, in described step (4), solvent for use includes water, benzene, toluene, isopropanol, n-hexane, hexamethylene, oil
Ether, ethyl acetate, tetrahydrofuran, 1-METHYLPYRROLIDONE, methyl alcohol, ethanol, N,N-dimethylformamide or dimethyl sulfoxide.
The beneficial effect of the inventive method, by high resolution mass spectrum, Pyrolysis Mass Spectrometry, nucleus magnetic hydrogen spectrum, carbon spectrum and infrared spectrum
Deng sign product structure, it was demonstrated that product is the aminopyrine of labeling.Qualitative analysis shows that the synthetic method can be obtained
Chemical purity reaches more than 99%, the product of stable isotope abundance more than 99%.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.
Embodiment 1
1 gram of 4-AA, 0.8 gram of 85% formic acid are added in 50ml round-bottomed flask, at 80 DEG C, react 5h.Continue
Addition 96% paraformaldehyde of 0.32g-13C, reacts 5h at 80 DEG C.Reaction terminates in back end hydrogenation sodium oxide molybdena and stirring half an hour, rotation
Dry, with n-hexane extraction 3 times.Precipitation, dries, recrystallisation from isopropanol, and activated carbon removes color, obtains final product product.Yield 85%.Purity
99%.Isotopic purity 99%.Structural characterization is as follows；
HRMS(ESI,m/z):[M+H]+, [M+Na]+, respectively 234.151148 and 256.133093, molecular formula is respectively
H18N3O12C11 13C2And H17N3NaO12C11 13C2.IRν(cm-1):1593rd, 1498,1448.75 (Ph), 1622.44 (C=C),
1658.85 (C=O), 1350 (C-N).1HNMR(CDCl3)δ：7.20～7.42 (m, 5H, C6H5N), 3.00～3.01 (s, 3H,
CH3NN),2.94(s,3H,13CH3NC), 2.55～2.56 (s, 3H,13CH3NC),2.19(s,3H,CH3C).13CNMR(CDCl3)
δ：163 (C=O), 124-150 (C6H5),128.9(NC-CH3), 124 (O=C-C=), 43 (N13CH3),36(CH3N),10.2
(CH3C=C).
Embodiment 2
1g 4-AA, 85% formic acid of 1.33g are added in 50ml round-bottomed flask, at 40 DEG C, react 8h.Continue
Continuous addition 96% paraformaldehyde of 0.48g-13C, reacts 5h at 80 DEG C.After reaction terminates plus in sodium carbonate and 0.5h is stirred, is spin-dried for,
With n-hexane extraction 3 times, precipitation, dry, benzene is recrystallized, activated carbon obtains product except color.Yield 92%.Purity 99%.Isotope
Purity 99%.Structural characterization result is with embodiment 1.
Embodiment 3
1g 4-AA, 85% formic acid of 1.33g are added in 50ml round-bottomed flask, at 60 DEG C, react 6h.Continue
Continuous addition 40% formaldehyde of 1.14g-13C solution, reacts 5h at 80 DEG C.After reaction terminates plus in sodium acid carbonate and 0.5h is stirred, revolve
Dry, with n-hexane extraction 3 times, precipitation, dry, hexamethylene is recrystallized, and activated carbon removes color, obtains final product product.Yield 85%.Purity
99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Embodiment 4
1g 4-AA, 85% formic acid of 1.33g are added in 50ml round-bottomed flask, at 150 DEG C, react 4h.Continue
Continuous addition 96% paraformaldehyde of 0.48g-13C, reacts 10h at 40 DEG C.Reaction terminates in back end hydrogenation sodium oxide molybdena and stirring 0.5h, rotation
Dry, with n-hexane extraction 3 times, then with ethyl alcohol recrystallization, activated carbon obtains product except color.Yield 80%.Purity 99%.Isotopically pure
Degree 99%.Structural characterization result is with embodiment 1.
Embodiment 5
Process is with embodiment 4, but the reaction temperature of two steps is changed to respectively, and 40 DEG C and 150 DEG C, other conditions are constant.
Yield 90%.Purity 99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Embodiment 6
Process is with embodiment 4, but the reaction temperature of two steps is changed to, and 150 DEG C and 150 DEG C, other conditions are constant.Yield
89%.Purity 99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Embodiment 7
1g 4-AA, 85% formic acid of 1.33g are added in 50ml round-bottomed flask, at 80 DEG C, react 9h.Continue
Continuous addition 96% paraformaldehyde of 0.48g-13C, reacts 5h at 80 DEG C.After reaction terminates plus in triethylamine and 0.5h is stirred, is spin-dried for,
With n-hexane extraction 3 times, precipitation, dry.Recrystallized with tetrahydrofuran, activated carbon removes color, obtains final product product.Yield 92%.Purity
99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Embodiment 8
Process is with embodiment 6, but will be changed to respectively 12h and 12h the reaction time.Yield 93%.Purity 99%.Same position
Plain purity 99%.Structural characterization result is with embodiment 1.
Embodiment 9
1g 4-AA, 85% formic acid of 1.33g are added in 50ml round-bottomed flask, at 80 DEG C, react 5h.Continue
Continuous addition 96% paraformaldehyde of 0.48g-13C, reacts 5h at 150 DEG C.After reaction terminates plus in methylamine and 0.5h is stirred, is spin-dried for,
Extracted 3 times with ether, precipitation, dry.With re crystallization from toluene, activated carbon removes color, obtains final product product.Yield 76%.Purity 99%.With
The plain purity 99% in position.Structural characterization result is with embodiment 1.
Embodiment 10
Process is with embodiment 9.But, extractant is changed to dichloromethane, and recrystallization solvent is changed to ethyl acetate.Yield
80%.Purity 99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Embodiment 11
Process is with embodiment 9.But, extractant is changed to chloroform, and recrystallization solvent is changed to tetrahydrofuran.Yield
85%.Purity 99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Embodiment 12
Process is with embodiment 9.But, extractant is changed to petroleum ether, and recrystallization solvent is changed to hexamethylene.Yield 82%.
Purity 99%.Isotopic purity 99%.Structural characterization result is with embodiment 1.
Above the present invention is explained, it is clear that if essentially without depart from the present invention inventive point and
Effect, will be readily apparent to persons skilled in the art deformation, also be all contained within protection scope of the present invention.
Claims (6)
1. a kind of synthetic method of the aminopyrine of labeling, it is characterised in that：The method comprising the steps of：
(1) 4-AA and formic acid are added in reaction vessel, heating response, obtain liquid I；
(2) in the liquid I obtained to step (1) add formaldehyde-13C or paraformaldehyde-13C, continues to react to obtain liquid II；
(3) the liquid II for obtaining step (2) is neutralized with alkali, then obtains solid I with organic solvent extraction, precipitation；
(4) the solid I solvent recrystallization that step (3) is obtained, activated carbon decolorizing, final product.
2. synthetic method according to claim 1, it is characterised in that the 4- amino peace in step (1) and (2) replace than
Woods, formic acid and formaldehyde-13C or paraformaldehyde-13C is the aqueous solution or solid reagent, the mol ratio 4-AA of three,
Formic acid and formaldehyde-13C is 1:3～5:2～3 or 4-AA, formic acid and paraformaldehyde-13C is 1:3～5:0.67～
1, and the solvent used by three is water or organic solvent.
3. synthetic method according to claim 1, it is characterised in that in step (1) and (2) reaction temperature be 40～
150℃.
4. synthetic method according to claim 1, it is characterised in that in step (1) and (2), reaction time are distinguished
For 1～12 hour.
5. synthetic method according to claim 1, it is characterised in that in step (3) alkali used be inorganic base or
Organic base；Organic solvent used include n-hexane, ether, petroleum ether, ethyl acetate, benzene,toluene,xylene, dichloromethane,
Chloroform or tetrachloromethane.
6. synthetic method according to claim 1, it is characterised in that in step (4) solvent for use include water, benzene,
Toluene, isopropanol, n-hexane, hexamethylene, petroleum ether, ethyl acetate, tetrahydrofuran, 1-METHYLPYRROLIDONE, methyl alcohol, ethanol,
N,N-dimethylformamide or dimethyl sulfoxide.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610862851.6A CN106478509A (en) | 2016-09-28 | 2016-09-28 | The synthetic method of the aminopyrine that a kind of carbon 13 is marked |
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| CN201610862851.6A CN106478509A (en) | 2016-09-28 | 2016-09-28 | The synthetic method of the aminopyrine that a kind of carbon 13 is marked |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1097357A (en) * | 1977-12-21 | 1981-03-10 | Hans J. Koch | Preparation of isotopically labelled aminopyrine |
| CN101891683A (en) * | 2010-07-22 | 2010-11-24 | 河北冀衡（集团）药业有限公司 | Aminopyrine production method |
| CN103588717A (en) * | 2013-11-27 | 2014-02-19 | 中国农业科学院植物保护研究所 | <13>C-labeled simazine synthesis method |
-
2016
- 2016-09-28 CN CN201610862851.6A patent/CN106478509A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1097357A (en) * | 1977-12-21 | 1981-03-10 | Hans J. Koch | Preparation of isotopically labelled aminopyrine |
| CN101891683A (en) * | 2010-07-22 | 2010-11-24 | 河北冀衡（集团）药业有限公司 | Aminopyrine production method |
| CN103588717A (en) * | 2013-11-27 | 2014-02-19 | 中国农业科学院植物保护研究所 | <13>C-labeled simazine synthesis method |
Non-Patent Citations (2)
| Title |
|---|
| E.JAGER-ROMAN ET AL.: "Development of N-Demethylase Activity Measured with the 13C-Aminopyrine Breath Test", 《EUR.J.PEDIATR.》 * |
| 上海第五制药厂: "氨基比林生产工艺改进", 《医药工业》 * |
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Application publication date: 20170308 |