CN105130862A - 1,3-bis(4-cyano-3-trifluoromethylphenyl)thiourea preparation method - Google Patents
1,3-bis(4-cyano-3-trifluoromethylphenyl)thiourea preparation method Download PDFInfo
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- CN105130862A CN105130862A CN201510482191.4A CN201510482191A CN105130862A CN 105130862 A CN105130862 A CN 105130862A CN 201510482191 A CN201510482191 A CN 201510482191A CN 105130862 A CN105130862 A CN 105130862A
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Abstract
The present invention relates to the field of chemistry, and discloses a 1,3-bis(4-cyano-3-trifluoromethylphenyl)thiourea preparation method, which comprises: 1, adding 1 mole of 4-amino-2-trifluoromethyl benzonitrile, 1-2.2 mole of diisopropylethylamine and 50 ml of dichloromethane to a reaction bottle; 2, adjusting the reaction system temperature to 20 DEG C, and adding 0.5 mole of thiophosgene in a dropwise manner; 3, controlling the reaction system to react for 2-3 h at a temperature of 20 DEG C; and 4, drying, and filtering the reaction solution to obtain the 1,3-bis(4-cyano-3-trifluoromethylphenyl)thiourea. According to the present invention, the preparation method has characteristics of reasonable synthesis route, cheap and easily available raw materials, simple and easy-performing operation, high yield and product purity meeting the requirement.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-.
Background technology
1, two (4-cyano group-3-trifluoromethyl) thiocarbamide of 3-is the major impurity that grace is mixed in Shandong amine (enzalutamide) building-up process, grace Shandong amine of mixing is developed cooperatively by Medivation company and Astellas (Astellas) company, chemical name is 4-［ 3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-4-oxo-2-thiocarbamoyl imidazole alkane-1-base ］ the fluoro-N-methyl-benzamide of-2-.Grace mix Shandong amine in Nikkei FDA (Food and Drug Adminstration) August 31 in 2012 (FDA) approval be used for the treatment of spread or recur late period male sex's castration tolerate prostate cancer (castration-resistantprostatecancer), commodity are called Xtandi, and this medicine is oral preparations.
Mix according to current synthesis grace the technique of Shandong amine, inevitably produce two (4-cyano group-3-trifluoromethyl) this impurity of thiocarbamide of 1,3-, the structural formula of two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-is:
，
By synthesizing this material and sample can effectively carry out in the analysis of foreign matter content grace Shandong amine of mixing as a comparison, but not yet there is its synthetic method of bibliographical information at present.
Summary of the invention
The problem of prior art in view of the above, the invention provides a kind of preparation method of 1,3-two (4-cyano group-3-trifluoromethyl) thiocarbamide that operation is simple.
Preparation method comprises the following steps:
(1) in reaction flask, the 4-amino-2-4-trifluoromethylbenzonitrile of 2 moles is added, the diisopropylethylamine of 2-4.4 mole and 50ml methylene dichloride;
(2), after temperature of reaction system being adjusted to 20 DEG C, the thiophosgene of 0.5 mole is dropped to;
(3) control reaction system and react 2-3 hour at 20 DEG C;
(4) dry, filtering reacting solution obtains two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-.
Preferably, step (3) also comprises employing HPLC tracking reaction until two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-no longer increases.
Preferably, in step (4), dry, filtering reacting solution, comprises the following steps: in reaction system, add 20ml water carry out layering, filters and obtains organic layer solution, organic over anhydrous dried over sodium sulfate 4h, filter vacuum concentrates dry doubling ethyl alcohol recrystallization the most at last.
Preferably, described step (1) adds the amount of diisopropylethylamine is 1-1.5 mole.
Prepared by aforesaid method 1,3-two (4-cyano group-3-trifluoromethyl) thiocarbamide, molar yield is 70%, purity is 99%.
The invention provides the preparation method of two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-, 4-amino-2-4-trifluoromethylbenzonitrile
, diisopropylethylamine DIPEA/CH
2cl
2with thiophosgene SCl
2two (4-cyano group-3-trifluoromethyl) thiocarbamide of Reactive Synthesis 1,3-
,
Synthetic route is as follows:
。
Accompanying drawing explanation
Fig. 1 is shown as 1,3-two (4-cyano group-3-trifluoromethyl) thiocarbamide nmr spectrum prepared by the present invention.
Embodiment
Below by way of specific specific examples, embodiments of the present invention are described, those skilled in the art the content disclosed by this specification sheets can understand other advantages of the present invention and effect easily.The present invention can also be implemented or be applied by embodiments different in addition, and the every details in this specification sheets also can based on different viewpoints and application, carries out various modification or change not deviating under spirit of the present invention.It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.Embodiment is a kind of preferred version of the present invention, not does any pro forma restriction to the present invention, also has other variant and remodeling under the prerequisite not exceeding the technical scheme described in requirement.
3.72g(2mmol is added in reaction flask) Compound II per, 2.71g(2.1mmol) diisopropylethylamine, 50ml methylene dichloride, is cooled to 20 DEG C, drips 1.14g(1mmol) thiophosgene.Be 20 DEG C in temperature to react 2 ~ 3 hours, HPLC follows the tracks of reaction until Compound II per reacts completely, 20ml water is added to reaction solution, layered filtration, organic over anhydrous dried over sodium sulfate 4h, by concentrated for filter vacuum dry, 20ml ethyl alcohol recrystallization obtains 1 of 2.9g, two (4-cyano group-3-trifluoromethyl) thiocarbamide of 3-, molar yield is 70%, purity is 99%.
Show in accompanying drawing 1:
Product
1h-NMR (400MHz, CDCl3) δ: 9.56 (s, 2H), 8.20 (d, J=2Hz, 2H), 7.98 (d, J=2Hz, 2H), 7.83 (d, J=8.4Hz, 2H) ppm.
Last it is noted that the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment to invention has been detailed description, for a person skilled in the art, it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein portion of techniques feature.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (4)
- The preparation method of two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1.1,3-, is characterized in that, comprise the steps:(1) in reaction flask, the 4-amino-2-4-trifluoromethylbenzonitrile of 2 moles is added, the diisopropylethylamine of 2-4.4 mole and 50ml methylene dichloride;(2), after temperature of reaction system being adjusted to 20 DEG C, the thiophosgene of 0.5 mole is dropped to;(3) control reaction system and react 2-3 hour at 20 DEG C;(4) dry, filtering reacting solution obtains two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-.
- 2. preparation method according to claim 1, is characterized in that, step (3) also comprises employing HPLC and follows the tracks of reaction until two (4-cyano group-3-trifluoromethyl) thiocarbamide of 1,3-no longer increases.
- 3. preparation method according to claim 1, it is characterized in that, dry, filtering reacting solution in step (4), comprise the following steps: in reaction system, add 20ml water carry out layering, filtration obtains organic layer solution, organic over anhydrous dried over sodium sulfate 4h, filter vacuum concentrates dry doubling ethyl alcohol recrystallization the most at last.
- 4. the preparation method according to any one of claims 1 to 3, is characterized in that, the amount adding diisopropylethylamine in described step (1) is 1-1.5 mole.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478477A (en) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | Grace miscellaneous Shandong amine midbody compound and preparation method thereof |
-
2015
- 2015-08-10 CN CN201510482191.4A patent/CN105130862A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478477A (en) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | Grace miscellaneous Shandong amine midbody compound and preparation method thereof |
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