CN102304085A - Process for synthesizing trigonelline hydrochloride from dimethyl carbonate and nicotinic acid - Google Patents
Process for synthesizing trigonelline hydrochloride from dimethyl carbonate and nicotinic acid Download PDFInfo
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- CN102304085A CN102304085A CN201110186086A CN201110186086A CN102304085A CN 102304085 A CN102304085 A CN 102304085A CN 201110186086 A CN201110186086 A CN 201110186086A CN 201110186086 A CN201110186086 A CN 201110186086A CN 102304085 A CN102304085 A CN 102304085A
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- nicotinic acid
- trigonelline
- methylcarbonate
- dimethyl carbonate
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Abstract
The invention relates to a process for synthesizing trigonelline hydrochloride from dimethyl carbonate and nicotinic acid. The process comprises the following steps of: reacting the nicotinic acid and the dimethyl carbonate in the presence of a catalyst K2CO3, after completely reacting, filtering and removing the K2CO3 and other undissolved substances, and decompressing, concentrating and removing the solvent, namely the dimethyl carbonate; dissolving the remained solid by using 4 mol/L of hydrochloric acid, adjusting pH to 2-3, and decompressing and removing the solvent; dissolving the remained solid by using proper absolute methanol, and filtering and removing the undissolved substances after standing; concentrating and crystallizing the filtrate, filtering to obtain solid, re-crystallizing the solid by using ethanol with a certain concentration, and obtaining the product. According to the process disclosed by the invention, the green methylated reagent, namely the dimethyl carbonate, for substituting the methylated reagents, such as dimethyl sulphate, halomethane and the like, which are poisonous on human bodies and risky on the environment, is reacted with the nicotinic acid; the green trigonelline hydrochloride is synthesized; the process condition is simple; the conversion rate of the nicotinic acid is high; the average substitution degree of the product is high; and the method is environment-friendly.
Description
Technical field
The present invention relates to a kind of synthesis technique of Trigonelline hydrochloride, relate in particular to and a kind ofly adopt green methylating reagent methylcarbonate to replace methylating reagents such as risky methyl-sulfate of toxic elements in human body and environment or halomethane are synthesized the methylcarbonate of green Trigonelline hydrochloride and the technology of nicotinic acid synthetic hydrochloric acid trigonelline.
Background technology
Trigonelline is present in fruit and the various plants such as the coffee berry of fabaceous seed, cucurbitaceous plant pumpkin; In the potato; Have hypoglycemic, reducing blood-fat, anticancer, promote nervous tissue regeneration, extensive pharmacological action such as calm, anti-oxidant, can be widely used in aspects such as medicine, additive.The toxic side effect of trigonelline is extremely low, has very high security.Commonly used being hydrochloric acid trigonelline (Trigonelline hydrochloride), is the N-methyl inner salt of nicotinic acid, its chemical structure as shown in Figure 1, molecular formula is C
7H
7NO
2Cl, molecular weight are 173.60, are needle-like or prismatic crystal, fusing point 258-259 ℃ (decomposition).Trigonelline has saline taste, and polarity is big, and is very easily water-soluble, is dissolved in ethanol, is insoluble to ether, benzene, chloroform.
Fig. 1. hydrochloric acid trigonelline chemical structure
At present, trigonelline mainly extracts from the Chinese medicine trigonella and obtains, but its content is low, only is 0.1037-0.3548%.If from trigonella, extract trigonelline, need the labor organic reagent, it is quite loaded down with trivial details to extract treating process, length consuming time, yield is very low, and cost is higher.Bibliographical information [Chen Weizhen is arranged recently; He Liqin; Wang Xiaoshan. the synthesising process research of sulfuric acid trigonelline. chemistry world; 2010; 51 (2): 108-109.] adopt the synthetic trigonelline of new chemistry route; With cheap methyl-sulfate is methylating reagent, and water is done the synthetic trigonelline of solvent, and sulfuric acid acidation gets its vitriol.Though this has been avoided existing document [Sarett HP; Perlzweig WA; Levy ED. Synthesis and excretion of trigonelline. Journal of Biological Chemistry; 1940; 135:483-485.] High Temperature High Pressure operation; Simplified operational condition, be convenient to reaction and follow the tracks of, yield brings up to 92% by original 65%.But use these toxicants of methyl-sulfate or halomethane, the risk that this has just increased the research and production processes has also restricted Trigonelline hydrochloride as medicine material medicine and Application of Additives.
And methylcarbonate is a kind of novel Green Chemistry reagent; Registered as non-toxicant in Europe in 1992; Contain the substitute that methyl can be used as methyl-sulfate, methyl halide in its molecular structure, higher than methyl-sulfate reaction yield, technology is simpler.We can reduce the production cost of Trigonelline hydrochloride, for suitability for industrialized production provides possible technological approaches through further optimizing synthetic technological condition greatly.The synthetic route of Trigonelline hydrochloride is seen Fig. 2.
Fig. 2. the synthetic route of Trigonelline hydrochloride.
Summary of the invention
The objective of the invention is to overcome the deficiency that exists in the prior art and provide a kind of and adopt green methylating reagent methylcarbonate to replace methylating reagents such as risky methyl-sulfate of toxic elements in human body and environment or halomethanes; React with nicotinic acid; The technology of synthetic green Trigonelline hydrochloride; Processing condition of the present invention are simple; The transformation efficiency of nicotinic acid is high; Purity is high, and is environmentally friendly.
The objective of the invention is to realize like this:
Technology with methylcarbonate and nicotinic acid synthetic hydrochloric acid trigonelline provided by the invention comprises the steps: at catalyzer K
2CO
3Exist down, nicotinic acid and dimethyl carbonate, the mol ratio of described nicotinic acid and methylcarbonate is 1:1-1:10, described nicotinic acid and K
2CO
3Mol ratio be: 1:1-1:5; After reacting completely, remove by filter K
2CO
3With other insolubles, concentrating under reduced pressure removes the methylcarbonate that desolvates; Residual solids is with 4 mol/L dissolving with hydrochloric acid and transfer pH, again removal of solvent under reduced pressure.Residual solids filters after leaving standstill and removes insolubles with an amount of anhydrous methanol dissolving.Filtrating concentrates crystallization, and suction filtration gets solid, and solid obtains product with the finite concentration ethyl alcohol recrystallization again.
In the step 1), temperature of reaction 0-100 ℃, reaction times 2-24 hour, complete with the thin-layer chromatography monitoring reaction.
The technology of methylcarbonate provided by the invention and nicotinic acid synthetic hydrochloric acid trigonelline has overcome oneself has the shortcoming of technology, replaces to methylating reagents such as risky methyl-sulfate of toxic elements in human body and environment or halomethanes, with K with green methylating reagent methylcarbonate
2CO
3Green Trigonelline hydrochloride has been synthesized in the cyclodextrin reaction.The present invention adopts single stage method, and processing step and condition are simple, and higher than methyl-sulfate reaction yield in addition except environmental protection, the transformation efficiency of nicotinic acid is high, and the transformation efficiency of reaction back nicotinic acid is 70-94.6%, and purity is high, and purity is 97.4-99.2%, and is environmentally friendly.
Embodiment
The present invention is described in detail as follows in conjunction with embodiment:
[embodiment one]
Have reflux condensing tube and stirring three mouthfuls at 100 ml and burn and add 49.24 g nicotinic acid (0.40 mo1) in the round-bottomed bottles, do to be stirred to dissolving in the solvent, add 55.28 g K with 67.41 ml (0.80 mol) methylcarbonate
2CO
3(0.40 mo1) continues to stir 10 minutes, 50 ℃ of heating in water bath controlled temperature, and reaction process is with thin-layer chromatography (TLC) monitoring reaction situation.After reaction finished, salt of wormwood K was removed in centrifugation
2CO
3, pressure is 150-260 Pa, and liquidus temperature is 60-85 ℃, and concentrating under reduced pressure is removed unreacted solvent methylcarbonate.Residual solids is with 4 mol/L dissolving with hydrochloric acid and transfer pH, again removal of solvent under reduced pressure.Residual solids adds an amount of shake well of anhydrous methanol, leaves standstill the back centrifugation and removes insolubles.Filtrating concentrates crystallization, and suction filtration gets solid, and solid gets product 54.51 g, trigonelline yield 78.5% 3 times with 50 ml, 70% ethyl alcohol recrystallization again.Degree of purity of production detects with high performance liquid chromatography and surveys, and purity is 97.4%.Through mass spectrum and proton nmr spectra conclusive evidence structure, the synthetic compound is consistent with the Trigonelline hydrochloride structure.EI-MS：
m/
z?(%)?138?[M+1]
+；1H?NMR：δ/′10
-6?4.38?(3H,?s,?N-CH3)，8.23?[s,?1H]，8.90?[dd,?1H]，9.17?[dd,?1H]，9.45?[s,?1H]。
Embodiment two]
Have reflux condensing tube and stirring three mouthfuls at 100 ml and burn and add 49.24 g nicotinic acid (0.40 mo1) in the round-bottomed bottles, do to be stirred to dissolving in the solvent, add 55.28 g K with 33.6 ml (0.88 mol) methylcarbonate
2CO
3(0.40 mo1) continues to stir 10 minutes, 50 ℃ of heating in water bath controlled temperature, and reaction process is with thin-layer chromatography monitoring reaction situation.After reaction finished, salt of wormwood K was removed in centrifugation
2CO
3, pressure is 150-260 Pa, and liquidus temperature is 60-85 ℃, and concentrating under reduced pressure is removed unreacted solvent methylcarbonate.Residual solids is with 4 mol/L dissolving with hydrochloric acid and transfer pH, again removal of solvent under reduced pressure.Residual solids adds an amount of shake well of anhydrous methanol, leaves standstill the back centrifugation and removes insolubles.Filtrating concentrates crystallization, and suction filtration gets solid, and solid gets product 57.08 g, trigonelline yield 82.2% 3 times with 50 ml, 70% ethyl alcohol recrystallization again.Degree of purity of production detects with high performance liquid chromatography and surveys, and purity is 98.5%.Through mass spectrum and proton nmr spectra conclusive evidence structure, the synthetic compound is consistent with the Trigonelline hydrochloride structure.
Embodiment three]
Have reflux condensing tube and stirring three mouthfuls at 100 ml and burn and add 49.24 g nicotinic acid (0.40 mo1) in the round-bottomed bottles, do to be stirred to dissolving in the solvent, add 66.34 g K with 33.6 ml (0.88 mol) methylcarbonate
2CO
3(0.48 mo1) continues to stir 10 minutes, 50 ℃ of heating in water bath controlled temperature, and reaction process is with thin-layer chromatography monitoring reaction situation.After reaction finished, salt of wormwood K was removed in centrifugation
2CO
3, pressure is 150-260 Pa, and liquidus temperature is 60-85 ℃, and concentrating under reduced pressure is removed unreacted solvent methylcarbonate.Residual solids is with 4 mol/L dissolving with hydrochloric acid and transfer pH, again removal of solvent under reduced pressure.Residual solids adds an amount of shake well of anhydrous methanol, leaves standstill the back centrifugation and removes insolubles.Filtrating concentrates crystallization, and suction filtration gets solid, and solid gets product 64.72 g, trigonelline yield 93.2% 3 times with 50 ml, 70% ethyl alcohol recrystallization again.Degree of purity of production detects with high performance liquid chromatography and surveys, and purity is 99.2%.Through mass spectrum and proton nmr spectra conclusive evidence structure, the synthetic compound is consistent with the Trigonelline hydrochloride structure.
Embodiment four]
Have reflux condensing tube and stirring three mouthfuls at 100 ml and burn and add 7.39 g nicotinic acid (0.06 mo1) in the round-bottomed bottles, do to be stirred to dissolving in the solvent, add 66.34 g K with 50.56 ml (0.60 mol) methylcarbonate
2CO
3(0.48 mo1) continues to stir 10 minutes, 50 ℃ of heating in water bath controlled temperature, and reaction process is with thin-layer chromatography monitoring reaction situation.After reaction finished, salt of wormwood K was removed in centrifugation
2CO
3, pressure is 150-260 Pa, and liquidus temperature is 60-85 ℃, and concentrating under reduced pressure is removed unreacted solvent methylcarbonate.Residual solids is with 4 mol/L dissolving with hydrochloric acid and transfer pH, again removal of solvent under reduced pressure.Residual solids adds an amount of shake well of anhydrous methanol, leaves standstill the back centrifugation and removes insolubles.Filtrating concentrates crystallization, and suction filtration gets solid, and solid gets product 7.84 g, trigonelline yield 94.6% 3 times with 10 ml, 70% ethyl alcohol recrystallization again.Degree of purity of production detects with high performance liquid chromatography and surveys, and purity is 99.0%.Through mass spectrum and proton nmr spectra conclusive evidence structure, the synthetic compound is consistent with the Trigonelline hydrochloride structure.
Embodiment five]
Have reflux condensing tube and stirring three mouthfuls at 100 ml and burn and add 49.24 g nicotinic acid (0.40 mo1) in the round-bottomed bottles, do to be stirred to dissolving in the solvent, add 276.4 g K with 84.266-33.6 ml (0.88 mol) methylcarbonate
2CO
3(4.0 mo1) continues to stir 10 minutes, 50 ℃ of heating in water bath controlled temperature, and reaction process is with thin-layer chromatography monitoring reaction situation.After reaction finished, salt of wormwood K was removed in centrifugation
2CO
3, pressure is 150-260 Pa, and liquidus temperature is 60-85 ℃, and concentrating under reduced pressure is removed unreacted solvent methylcarbonate.Residual solids is with 4 mol/L dissolving with hydrochloric acid and transfer pH, again removal of solvent under reduced pressure.Residual solids adds an amount of shake well of anhydrous methanol, leaves standstill the back centrifugation and removes insolubles.Filtrating concentrates crystallization, and suction filtration gets solid, and solid gets product 56.73 g, trigonelline yield 81.7% 3 times with 50 ml, 70% ethyl alcohol recrystallization again.Degree of purity of production detects with high performance liquid chromatography and surveys, and purity is 99.1%.Through mass spectrum and proton nmr spectra conclusive evidence structure, the synthetic compound is consistent with the Trigonelline hydrochloride structure.
Claims (3)
1. the technology of methylcarbonate and nicotinic acid synthetic hydrochloric acid trigonelline is characterized in that: comprise the steps:
1), at temperature of reaction and K
2CO
3Exist down, nicotinic acid and dimethyl carbonate, the mol ratio of described nicotinic acid and methylcarbonate is 1:1-1:10, described nicotinic acid and K
2CO
3Mol ratio be: 1:1-1:5;
2), question response fully after, remove by filter K
2CO
3With other insolubles, concentrating under reduced pressure removes the methylcarbonate that desolvates; Residual solids is with the dissolving with hydrochloric acid of 4 mol/L, and accent pH2-3, removal of solvent under reduced pressure again;
3), residual solids is with the dissolving of an amount of anhydrous methanol, leave standstill the back suction filtration and remove insolubles; Filtrating concentrates crystallization, and suction filtration gets solid, and solid obtains product with the finite concentration ethyl alcohol recrystallization again.
2. the technology of methylcarbonate according to claim 1 and nicotinic acid synthetic hydrochloric acid trigonelline is characterized in that: the temperature of reaction of said step 1) is 0-100 ℃, and whether the reaction times is 2-24 hour, complete with the thin-layer chromatography monitoring reaction.
3. the technology of methylcarbonate according to claim 1 and 2 and nicotinic acid synthetic hydrochloric acid trigonelline is characterized in that: said step 2) remove by filter K
2CO
3With the pressure of other insolubles be 150-260 Pa, liquidus temperature is 60-85 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113277977A (en) * | 2021-05-25 | 2021-08-20 | 德锡化学(山东)有限公司 | Trigonelline compound and synthesis method and application thereof |
| WO2022097017A1 (en) * | 2020-11-05 | 2022-05-12 | Laurus Labs Limited | An improved process for the preparation of trigonelline or pharmaceutically acceptable salts thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1425003A (en) * | 2000-04-19 | 2003-06-18 | 霍夫曼-拉罗奇有限公司 | Methylation of indole compounds from dimethyl carbonate |
| WO2010042750A2 (en) * | 2008-10-09 | 2010-04-15 | Aaron David Redish | System and method for miniature wireless implantable probe |
| CN101967121A (en) * | 2010-06-28 | 2011-02-09 | 南京泽朗医药科技有限公司 | Process for extracting trigonelline |
-
2011
- 2011-07-05 CN CN201110186086A patent/CN102304085A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1425003A (en) * | 2000-04-19 | 2003-06-18 | 霍夫曼-拉罗奇有限公司 | Methylation of indole compounds from dimethyl carbonate |
| WO2010042750A2 (en) * | 2008-10-09 | 2010-04-15 | Aaron David Redish | System and method for miniature wireless implantable probe |
| CN101967121A (en) * | 2010-06-28 | 2011-02-09 | 南京泽朗医药科技有限公司 | Process for extracting trigonelline |
Non-Patent Citations (1)
| Title |
|---|
| 陈维珍等: "硫酸葫芦巴碱的合成工艺研究", 《化学世界》, no. 2, 31 December 2010 (2010-12-31) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022097017A1 (en) * | 2020-11-05 | 2022-05-12 | Laurus Labs Limited | An improved process for the preparation of trigonelline or pharmaceutically acceptable salts thereof |
| CN113277977A (en) * | 2021-05-25 | 2021-08-20 | 德锡化学(山东)有限公司 | Trigonelline compound and synthesis method and application thereof |
| CN113277977B (en) * | 2021-05-25 | 2022-10-04 | 德锡化学(山东)有限公司 | Trigonelline compound and synthesis method and application thereof |
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Application publication date: 20120104 |