CN105541724A - Preparation method of methimazole - Google Patents
Preparation method of methimazole Download PDFInfo
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- CN105541724A CN105541724A CN201610039982.4A CN201610039982A CN105541724A CN 105541724 A CN105541724 A CN 105541724A CN 201610039982 A CN201610039982 A CN 201610039982A CN 105541724 A CN105541724 A CN 105541724A
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- thiamazole
- reaction
- reaction solution
- butyl lithium
- methylimidazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/84—Sulfur atoms
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Abstract
The invention relates to a preparation method of methimazole. The method specifically comprises the following step: enabling reaction of N-methylimidazole, N-butyllithium and powdered sulfur in an organic solvent to obtain methimazole. The preparation method disclosed by the invention is simple in process, mild in condition, simple to operate, easy for post treatment, applicable for industrialized production, and capable of greatly improving the reaction yield of methimazole.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of preparation method of Thiamazole.
Background technology
Thiamazole (Methimazole) is antithyroid drug.Be applicable to various types of hyperthyroidism, be particularly useful for: the state of an illness is comparatively light, the mild to moderate enlargement patient of Tiroidina; Teenager, children and gerontal patient; Recur after thyroid operation, be unsuitable for again with radioactivity iodine-131 curer; Pre-operative preparation and the assisting therapy as iodine-131 radiotherapy.
In prior art, the people (J.Org.Chem.1994,59,4691-4692) such as Guziec discloses a kind of preparation method of Thiamazole, with N-Methylimidazole for raw material, react with n-Butyl Lithium, and then add sulphur powder back flow reaction, finally obtain the yield 42% of Thiamazole crude product.The method severe reaction conditions, drips n-Butyl Lithium at-78 DEG C, is difficult to industrial amplification production, and aftertreatment employing shrend is gone out after acid adjustment, needs to use chloroform and extracts.Chloroform is two classes and easily makes malicious solvent, should limit use, and chloroform is genetoxic caution structure material equally, should avoid using in pharmaceutical synthesis.
Therefore, the preparation method of existing Thiamazole still haves much room for improvement.
Summary of the invention
The present invention is intended to solve one of technical problem in correlation technique at least to a certain extent.Object of the present invention is exactly for prior art defect, provides that a kind of technique is simple, mild condition, is applicable to the Thiamazole preparation method of suitability for industrialized production completely.
According to an aspect of the present invention, the invention provides a kind of method preparing Thiamazole, comprising: N-Methylimidazole is dissolved in the first organic solvent by (1), to obtain the first reaction solution, n-Butyl Lithium is dissolved in a second organic solvent, to obtain the second reaction solution; (2) at-15 DEG C ~ 0 DEG C, described second reaction solution drops in described first reaction solution, and insulation reaction, after 0.5 ~ 2 hour, adds elemental sulfur, to obtain the 3rd reaction solution; (3) by described 3rd reaction solution temperature rising reflux reaction 6 ~ 10 hours, with ice-water bath cancellation reaction, add dilute hydrochloric acid and regulate pH to be 5.0 ~ 7.0, to obtain the 4th reaction solution; (4) described 4th reaction solution is concentrated, to obtain the solid after concentrating; (5) solid after described concentrating, gac are added in ethyl acetate, carry out heating for dissolving, return stirring 1 hour, filter, to obtain filtrate; (6) described filtrate is carried out concentrating under reduced pressure, to obtain Thiamazole.Contriver finds through overtesting, the dropping temperature of n-Butyl Lithium is increased to-15 DEG C ~ 0 DEG C by-78 DEG C, elemental sulfur adds temperature and keeps identical with n-Butyl Lithium, good reaction environment can be provided thus for N-Methylimidazole and n-Butyl Lithium and sulphur powder, and then improve the yield of Thiamazole, what reaction yield can be reported by prior art obtains Thiamazole crude yield 42%, is increased to the highly finished product yield after refining of Thiamazole in the technology of the present invention more than 79%.Further, utilize the Thiamazole that the inventive method prepares, its purity is high, all reaches more than 99%.
According to some embodiments of the present invention, described first organic solvent is tetrahydrofuran (THF).Thus, a large amount of uses of the unfriendly solvent-chloroform of environment are avoided.
According to some embodiments of the present invention, described second organic solvent is normal hexane.
According to some embodiments of the present invention, N-Methylimidazole: n-Butyl Lithium: the mol ratio of elemental sulfur is 1:(1.2 ~ 1.3): (1.2 ~ 1.4).Contriver is surprised to find that, participate in the N-Methylimidazole of reaction and n-Butyl Lithium and sulphur powder with 1:(1.2 ~ 1.3): the mol ratio of (1.2 ~ 1.4) feeds intake, N-Methylimidazole and n-Butyl Lithium and sulphur powder can be made fully to be reacted in the first organic solvent, and then improve the productive rate of Thiamazole.
According to some embodiments of the present invention, N-Methylimidazole: n-Butyl Lithium: the mol ratio of elemental sulfur is 1:1.25:1.30.Contriver is surprised to find that, when the N-Methylimidazole of participation reaction and the mol ratio of n-Butyl Lithium and sulphur powder are 1:1.25:1.30, N-Methylimidazole and n-Butyl Lithium and sulphur powder can be made fully to be reacted in the first organic solvent, and then improve the productive rate of Thiamazole.
Preparation method of the present invention has following advantage: (1) its aftertreatment is simple, eliminate loaded down with trivial details extraction and washing operation step, avoid a large amount of uses of the unfriendly solvent-chloroform of environment, overcome the difficulty that the former is difficult to realize suitability for industrialized production, and achieve useful effect; (2) simple, the mild condition of technique, easy and simple to handle, is easy to aftertreatment, is applicable to industrialized production; (3) reaction yield and the purity of Thiamazole is substantially increased, what the reaction yield of Thiamazole was reported by prior art by it obtains Thiamazole crude yield 42% (its refining rear yield is certain to lower than 42%), be increased to the highly finished product yield after refining of Thiamazole in the technology of the present invention more than 79%, further, the Thiamazole utilizing the inventive method to prepare is relative to prior art, and it is high by the purity of gas chromatographic detection.
Accompanying drawing explanation
Fig. 1 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 1;
Fig. 2 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 2;
Fig. 3 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 3;
Fig. 4 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 4;
Fig. 5 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 5;
Fig. 6 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 6;
Fig. 7 is the gas chromatogram preparing Thiamazole according to the embodiment of the present invention 7; And
Fig. 8 is the gas chromatogram preparing Thiamazole according to comparative example 1 of the present invention.
Embodiment
The concrete preparation method of the present invention is as follows:
N-Methylimidazole is dissolved in tetrahydrofuran (THF), at-15 DEG C ~ 0 DEG C, drip n-Butyl Lithium-hexane solution, then insulation reaction 0.5 ~ 2 hour.Then add elemental sulfur at such a temperature, temperature rising reflux reaction 6 ~ 10 hours after reinforced, thin-layer chromatography detects extremely without raw material spot, and then cancellation reaction under ice-water bath, adds dilute hydrochloric acid and regulate pH to be 5.0 ~ 7.0, then reaction system be concentrated into dry in batches.Solid after concentrated is added ethyl acetate and heating activated carbon dissolving, and return stirring 1 hour, filters, obtains Thiamazole after filtrate reduced in volume.
Synthetic route of the present invention is as follows:
We find unexpectedly, the present invention participates in the N-Methylimidazole that reacts and n-Butyl Lithium and sulphur powder with 1:(1.2 ~ 1.3): the mol ratio of (1.2 ~ 1.4) feeds intake, when the mol ratio of N-Methylimidazole and n-Butyl Lithium and sulphur powder is 1:1.25:1.30, N-Methylimidazole and n-Butyl Lithium and sulphur powder can be made fully to be reacted in tetrahydrofuran (THF), and then improve the productive rate of Thiamazole.
The present inventor finds through overtesting, the dropping temperature of n-Butyl Lithium is increased to-15 DEG C ~ 0 DEG C by-78 DEG C, elemental sulfur adds temperature and keeps identical with n-Butyl Lithium, good reaction environment can be provided thus for N-Methylimidazole and n-Butyl Lithium and sulphur powder, and then improve the yield of Thiamazole, what reaction yield can be reported by prior art obtains Thiamazole crude yield 42%, is increased to the highly finished product yield after refining of Thiamazole in the technology of the present invention more than 79%.And the Thiamazole that the inventive method prepares, its purity is high, all reaches more than 99%.
Preparation method of the present invention, its aftertreatment is simple, eliminates loaded down with trivial details extraction and washing operation step, avoids a large amount of uses of the unfriendly solvent-chloroform of environment, overcome the difficulty that the former is difficult to realize suitability for industrialized production, and achieve useful effect.Preparation method of the present invention, technique is simple, mild condition, easy and simple to handle, is easy to aftertreatment, is applicable to industrialized production.And preparation method of the present invention, substantially increase the reaction yield of Thiamazole, what the reaction yield of Thiamazole was reported by prior art by it obtains Thiamazole crude yield 42% (its refining after yield be certain to lower than 42%), to be increased in the technology of the present invention the highly finished product yield of Thiamazole after refining more than 79%.And the Thiamazole that the inventive method prepares is relative to prior art, and it is high by the purity of gas chromatographic detection.
Embodiment
Embodiment is used for describing the present invention further below, but does not impose any restrictions.
Embodiment 1
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then be cooled to-15 DEG C and drip n-Butyl Lithium-hexane solution 48 milliliters (containing n-Butyl Lithium 120mmoL, 2.5moL/L),-15 DEG C of insulation reaction 2 hours after dripping, then add 3.84 grams of (120mmoL) elemental sulfurs at this temperature in batches, add the rear stirring at room temperature that slowly rises to and react 10 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 5.0 ~ 5.5, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.04 grams, yield 79.30%, purity 99.42% (gas chromatographic detection).
Embodiment 2
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then be cooled to-10 DEG C and drip n-Butyl Lithium-hexane solution 48 milliliters (containing n-Butyl Lithium 120mmoL, 2.5moL/L), after dripping at-10 DEG C insulation reaction 1.5 hours, then add 4.48 grams of (140mmoL) elemental sulfurs at such a temperature in batches, add rear temperature rising reflux and react 9 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 5.5 ~ 6.0, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.52 grams, yield 83.51%, purity 99.49% (gas chromatographic detection).
Embodiment 3
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then be cooled to-5 DEG C and drip n-Butyl Lithium-hexane solution 52 milliliters (containing n-Butyl Lithium 130mmoL, 2.5moL/L), after dripping at-5 DEG C insulation reaction 1 hour, then add 3.84 grams of (120mmoL) elemental sulfurs at such a temperature in batches, add rear temperature rising reflux and react 8 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 6.0 ~ 6.5, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.31 grams, yield 81.67%, purity 99.03% (gas chromatographic detection).
Embodiment 4
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then n-Butyl Lithium-hexane solution 52 milliliters is dripped at being cooled to 0 DEG C (containing n-Butyl Lithium 130mmoL, 2.5moL/L), after dripping at 0 DEG C insulation reaction 0.5 hour, then add 4.48 grams of (140mmoL) elemental sulfurs at such a temperature in batches, add rear temperature rising reflux and react 6 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 6.5 ~ 7.0, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.11 grams, yield 79.91%, purity 99.12% (gas chromatographic detection).
Embodiment 5
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then be cooled to-5 DEG C and drip n-Butyl Lithium-hexane solution 50 milliliters (containing n-Butyl Lithium 125mmoL, 2.5moL/L), after dripping at-5 DEG C insulation reaction 1 hour, then add 4.16 grams of (130mmoL) elemental sulfurs at such a temperature in batches, add rear temperature rising reflux and react 8 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 6.0 ~ 6.5, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.41 grams, yield 82.54%, purity 100% (gas chromatographic detection).
Embodiment 6
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then be cooled to-10 DEG C and drip n-Butyl Lithium-hexane solution 50 milliliters (containing n-Butyl Lithium 125mmoL, 2.5moL/L), after dripping at-10 DEG C insulation reaction 1.5 hours, then add 4.00 grams of (125mmoL) elemental sulfurs at such a temperature in batches, add rear temperature rising reflux and react 9 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 5.5 ~ 6.0, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.26 grams, yield 81.23%, purity 99.67% (gas chromatographic detection).
Embodiment 7
N-Methylimidazole 8.21 grams (100mmoL) and 80 milliliters of tetrahydrofuran (THF)s are joined in three mouthfuls of reaction flasks, then n-Butyl Lithium-hexane solution 50 milliliters is dripped at being cooled to 0 DEG C (containing n-Butyl Lithium 125mmoL, 2.5moL/L), after dripping at 0 DEG C insulation reaction 0.5 hour, then add 4.32 grams of (135mmoL) elemental sulfurs at such a temperature in batches, add rear temperature rising reflux and react 6 hours.Thin-layer chromatography detects extremely without raw material spot, then cancellation under ice-water bath, adds dilute hydrochloric acid and regulates pH to 6.5 ~ 7.0, is then concentrated into dry by reaction system pressurization.Then the solid after concentrated is added ethyl acetate and heating activated carbon dissolves, reflux decolour about 1 hour, filter, filtrate reduced in volume obtains faint yellow Thiamazole solid 9.20 grams, yield 80.70%, purity 99.63% (gas chromatographic detection).
Comparative example 1
In comparative example 1, the preparation method of Thiamazole crude product is with reference to prior art (J.Org.Chem.1994,59,4691-4692) prepare, then Thiamazole crude solid is added ethyl acetate and heating activated carbon dissolving, reflux decolour about 1 hour, filters, filtrate reduced in volume obtains faint yellow Thiamazole solid, measures purity 93.42% (gas chromatographic detection).
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
Claims (5)
1. prepare a method for Thiamazole, it is characterized in that: comprising:
(1) N-Methylimidazole is dissolved in the first organic solvent, to obtain the first reaction solution, n-Butyl Lithium is dissolved in a second organic solvent, to obtain the second reaction solution;
(2) at-15 DEG C ~ 0 DEG C, described second reaction solution drops in described first reaction solution, and insulation reaction, after 0.5 ~ 2 hour, adds elemental sulfur, to obtain the 3rd reaction solution;
(3) by described 3rd reaction solution temperature rising reflux reaction 6 ~ 10 hours, with ice-water bath cancellation reaction, add dilute hydrochloric acid and regulate pH to be 5.0 ~ 7.0, to obtain the 4th reaction solution;
(4) described 4th reaction solution is concentrated, to obtain the solid after concentrating;
(5) solid after described concentrating, gac are added in ethyl acetate, carry out heating for dissolving, return stirring 1 hour, filter, to obtain filtrate;
(6) described filtrate is carried out concentrating under reduced pressure, to obtain Thiamazole.
2. method according to claim 1, is characterized in that, described first organic solvent is tetrahydrofuran (THF).
3. method according to claim 1, is characterized in that, described second organic solvent is normal hexane.
4. method according to claim 1, is characterized in that, N-Methylimidazole: n-Butyl Lithium: the mol ratio of elemental sulfur is 1:(1.2 ~ 1.3): (1.2 ~ 1.4).
5. method according to claim 4, is characterized in that, N-Methylimidazole: n-Butyl Lithium: the mol ratio of elemental sulfur is 1:1.25:1.30.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107522661A (en) * | 2017-10-10 | 2017-12-29 | 浦拉司科技（上海）有限责任公司 | A kind of preparation method of the alkyl imidazole of 2 sulfydryl 1 |
| CN108558744A (en) * | 2018-07-04 | 2018-09-21 | 常州大学 | A kind of preparation method of 2- methoxyl groups -4- trifluoromethyl -3- pyridine sulfonyl chlorides |
| CN115784999A (en) * | 2022-12-19 | 2023-03-14 | 烟台大学 | Optical induction preparation of imidazole-2-thione and derivatives thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107522661A (en) * | 2017-10-10 | 2017-12-29 | 浦拉司科技（上海）有限责任公司 | A kind of preparation method of the alkyl imidazole of 2 sulfydryl 1 |
| CN107522661B (en) * | 2017-10-10 | 2020-01-07 | 浦拉司科技（上海）有限责任公司 | Preparation method of 2-mercapto-1-alkyl imidazole |
| CN108558744A (en) * | 2018-07-04 | 2018-09-21 | 常州大学 | A kind of preparation method of 2- methoxyl groups -4- trifluoromethyl -3- pyridine sulfonyl chlorides |
| CN115784999A (en) * | 2022-12-19 | 2023-03-14 | 烟台大学 | Optical induction preparation of imidazole-2-thione and derivatives thereof |
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