CN105294575A - Preparation method of methyl orotate - Google Patents
Preparation method of methyl orotate Download PDFInfo
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- CN105294575A CN105294575A CN201510883251.3A CN201510883251A CN105294575A CN 105294575 A CN105294575 A CN 105294575A CN 201510883251 A CN201510883251 A CN 201510883251A CN 105294575 A CN105294575 A CN 105294575A
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- preparation
- vitamin
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- thionyl chloride
- methyl esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of methyl orotate. The preparation method comprises the following steps: adding orotic acid, toluene and N,N-dimethylformamide to a reaction vessel, dropwise adding slightly excessive thionyl chloride and carrying out reflux reaction, thus preparing an acyl chlorination intermediate; dropwise adding ethanol to the reaction system, carrying out reflux reaction and carrying out cooling and suction filtration, thus preparing methyl orotate. The preparation method has the beneficial effects that the green and clean process production technology is adopted; orotic acid is used as the raw material, toluene is used as a solvent and slightly excessive thionyl chloride is added to carry out acyl chlorination to prepare the acyl chloride intermediate, thus reducing the usage amount of thionyl chloride, solving the problems of high operating labor intensity and severe pollution caused because excessive thionyl chloride needs to be removed through distillation and providing technical support for the economical, environment-friendly and clean process production technology and volume production of methyl orotate.
Description
Technical field
The present invention relates to a kind of preparation method of vitamin B13 methyl esters.
Background technology
Vitamin B13 methyl esters, as the key intermediate preparing polypeptide compound series, has its preparation method of many bibliographical informations, mainly contains Fischer esterification method and chloride method.Wherein vitamin B13 and methyl alcohol are directly carried out reversible reaction when hydrogenchloride is catalyzer, long reaction time by Fischer esterification method, and temperature of reaction is high, and yield is low; And by sulfur oxychloride chloride esterification process, excessive sulfur oxychloride needs to steam before esterification to remove, labour intensity is large, and raw material consumption is many, can produce more pollution, is difficult to amplify produce.
Summary of the invention
The technical problem to be solved in the present invention is: based on the problems referred to above, the invention provides a kind of preparation method of vitamin B13 methyl esters.
The present invention solves the technical scheme that its technical problem adopts: a kind of preparation method of vitamin B13 methyl esters, comprises the following steps:
(1) preparation of vitamin B13 chloride intermediate: add vitamin B13, toluene and DMF in reaction vessel, stirs and is warming up to 80 DEG C, drip micro-excessive sulfur oxychloride, after dropwising, be warming up to 110 DEG C of back flow reaction 8h, obtained chloride intermediate;
(2) preparation of vitamin B13 methyl esters: be cooled to 60 DEG C, drips methyl alcohol in the reaction system of step (1), after dropwising, is warming up to 80 DEG C of back flow reaction 2h, cooling suction filtration, obtain whey acid methyl esters.
Further, in step (1), the mol ratio of vitamin B13 and sulfur oxychloride is 1:1.2 ~ 1:1.4, and DMF is catalytic amount.
Further, in step (2), the mol ratio of methyl alcohol and chloride intermediate is 5.6:1 ~ 6.5:1.
The invention has the beneficial effects as follows: adopt green cleaning procedure production technology, vitamin B13 is raw material, toluene is as solvent, add sulfur oxychloride excessive in a subtle way to carry out chloride and make acyl chlorides intermediate, decrease the consumption of sulfur oxychloride, solving excess thionyl chloride, to need to steam the operation labour intensity that removes large and pollute the problems such as large, to economic environment-friendly clean process production technology, for batch production vitamin B13 methyl esters provides technical guarantee.
Embodiment
The invention will be further described in conjunction with specific embodiments now, and following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment 1
In 500mL four-hole boiling flask, drop into vitamin B13 (78.0g, 0.50mol), toluene (200g), 5 DMFs, stir and be warming up to 80 DEG C.80 DEG C start to drip sulfur oxychloride (77.5g, 0.65mol), have HCl gas to emerge (note HCl gas dry and reclaim) during dropping, and when temperature is raised to 83 DEG C, bubble becomes large, continue to drip about within 1.5 hours, to dropwise.After dropwising, 110 DEG C of temperature rising reflux reactions 8h, TLC confirm to remain without raw material, obtained chloride intermediate.
After reaction terminates, nitrogen protection borehole cooling to 60 DEG C, drips excessive methanol (90.0g, 2.8mol), heat release in former reaction system, and after dropwising, 80 DEG C of temperature rising reflux reactions 2h, TLC confirm without chloride intermediate.Reaction terminates rear cooling suction filtration, and with anhydrous methanol washing, dries to obtain dry product.With recrystallizing methanol, filtration, drying, obtain vitamin B13 methyl esters 81.3g.The yield of whole reaction is 95.6%.The atlas analysis data of vitamin B13 methyl esters are: 1HNMR (DMSO), δ (ppm): 3.821 (s, 3H, CH3), 6.025 (d, 1H, Py-H), 11.146 (s, 1H, OH), 11.393 (s, 1H, OH).
Embodiment 2
In 500mL four-hole boiling flask, drop into vitamin B13 (78.0g, 0.50mol), toluene (200g), 5 DMFs, stir and be warming up to 80 DEG C.80 DEG C start to drip sulfur oxychloride (71.5g, 0.60mol), have HCl gas to emerge (note HCl gas dry and reclaim) during dropping, and when temperature is raised to 83 DEG C, bubble becomes large, continue to drip about within 1.5 hours, to dropwise.After dropwising, 80 DEG C of temperature rising reflux reactions 8h, TLC confirm to remain without raw material, obtained chloride intermediate.
After reaction terminates, nitrogen protection borehole cooling to 60 DEG C, drips excessive methanol (90.0g, 2.8mol), heat release in former reaction system, and after dropwising, 80 DEG C of temperature rising reflux reactions 2h, TLC confirm without chloride intermediate.Reaction terminates rear cooling suction filtration, and with anhydrous methanol washing, dries to obtain dry product.With recrystallizing methanol, filtration, drying, obtain vitamin B13 methyl esters 75.8g.The yield of whole reaction is 89.2%.The atlas analysis data of vitamin B13 methyl esters are: 1HNMR (DMSO), δ (ppm): 3.821 (s, 3H, CH3), 6.025 (d, 1H, Py-H), 11.146 (s, 1H, OH), 11.393 (s, 1H, OH).
Embodiment 3
In 500mL four-hole boiling flask, drop into vitamin B13 (78.0g, 0.50mol), toluene (200g), 5 DMFs, stir and be warming up to 80 DEG C.80 DEG C start to drip sulfur oxychloride (83.5g, 0.70mol), have HCl gas to emerge (note HCl gas dry and reclaim) during dropping, and when temperature is raised to 83 DEG C, bubble becomes large, continue to drip about within 1.5 hours, to dropwise.After dropwising, 110 DEG C of temperature rising reflux reactions 8h, TLC confirm to remain without raw material, obtained chloride intermediate.
After reaction terminates, nitrogen protection borehole cooling to 60 DEG C, drips excessive methanol (90.0g, 2.8mol), heat release in former reaction system, and after dropwising, 80 DEG C of temperature rising reflux reactions 2h, TLC confirm without chloride intermediate.Reaction terminates rear cooling suction filtration, and with anhydrous methanol washing, dries to obtain dry product.With recrystallizing methanol, filtration, drying, obtain vitamin B13 methyl esters 80.2g.The yield of whole reaction is 94.4%.The atlas analysis data of vitamin B13 methyl esters are: 1HNMR (DMSO), δ (ppm): 3.821 (s, 3H, CH3), 6.025 (d, 1H, Py-H), 11.146 (s, 1H, OH), 11.393 (s, 1H, OH).
With above-mentioned according to desirable embodiment of the present invention for enlightenment, by above-mentioned description, relevant staff in the scope not departing from this invention technological thought, can carry out various change and amendment completely.The technical scope of this invention is not limited to the content on specification sheets, must determine its technical scope according to right.
Claims (3)
1. a preparation method for vitamin B13 methyl esters, is characterized in that: comprise the following steps:
(1) preparation of vitamin B13 chloride intermediate: add vitamin B13, toluene and DMF in reaction vessel, stirs and is warming up to 80 DEG C, drip micro-excessive sulfur oxychloride, after dropwising, be warming up to 110 DEG C of back flow reaction 8h, obtained chloride intermediate;
(2) preparation of vitamin B13 methyl esters: be cooled to 60 DEG C, drips methyl alcohol in the reaction system of step (1), after dropwising, is warming up to 80 DEG C of back flow reaction 2h, cooling suction filtration, obtain whey acid methyl esters.
2. the preparation method of a kind of vitamin B13 methyl esters according to claim 1, is characterized in that: in described step (1), the mol ratio of vitamin B13 and sulfur oxychloride is 1: 1.2 ~ 1: 1.4, and DMF is catalytic amount.
3. the preparation method of a kind of vitamin B13 methyl esters according to claim 1, is characterized in that: in described step (2), the mol ratio of methyl alcohol and chloride intermediate is 5.6: 1 ~ 6.5: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510883251.3A CN105294575A (en) | 2015-12-03 | 2015-12-03 | Preparation method of methyl orotate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510883251.3A CN105294575A (en) | 2015-12-03 | 2015-12-03 | Preparation method of methyl orotate |
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| Publication Number | Publication Date |
|---|---|
| CN105294575A true CN105294575A (en) | 2016-02-03 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510883251.3A Pending CN105294575A (en) | 2015-12-03 | 2015-12-03 | Preparation method of methyl orotate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009076743A1 (en) * | 2007-12-18 | 2009-06-25 | Iovate T. & P. Inc. | Preparations containing amino acids and orotic acid |
| CN102574837A (en) * | 2009-10-27 | 2012-07-11 | 德尔塔菲制药股份有限公司 | Novel 5-fluorouracil derivative |
-
2015
- 2015-12-03 CN CN201510883251.3A patent/CN105294575A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009076743A1 (en) * | 2007-12-18 | 2009-06-25 | Iovate T. & P. Inc. | Preparations containing amino acids and orotic acid |
| CN102574837A (en) * | 2009-10-27 | 2012-07-11 | 德尔塔菲制药股份有限公司 | Novel 5-fluorouracil derivative |
Non-Patent Citations (2)
| Title |
|---|
| HERMAN GERSHON,: "Pyrimidines. II. Chlorinated pyrimidines derived from orotic acid", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 孙昌俊，等: "《药物合成反应——理论与实践》", 31 May 2007 * |
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Application publication date: 20160203 |
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