CN104610111A - Preparation method of 3-fluoro-4-methylphenylisothiocyanate - Google Patents
Preparation method of 3-fluoro-4-methylphenylisothiocyanate Download PDFInfo
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- CN104610111A CN104610111A CN201410829298.7A CN201410829298A CN104610111A CN 104610111 A CN104610111 A CN 104610111A CN 201410829298 A CN201410829298 A CN 201410829298A CN 104610111 A CN104610111 A CN 104610111A
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Abstract
The invention discloses a preparation method of 3-fluoro-4-methylphenylisothiocyanate. The preparation method comprises the following steps: (1) reacting 4-amino-2-(trifluoromethyl)benzonitrile as shown in the formula (I) with triethylene diamine and carbon disulfide to obtain a compound (II); (2) reacting the compound (II) with BTC to obtain the 3-fluoro-4-methylphenylisothiocyanate as shown in the formula (III); the reaction formula is shown in the Specification. The preparation method disclosed by the invention is simple in operation, high in safety and low in production cost, and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of the different Thiocyanato of a kind of 4--2-(trifluoromethyl) cyanobenzene (CAS Registry Number:143782-23-4).
Background technology
Grace Shandong amine (enzalutamide) of mixing is developed cooperatively by Medivation company and Astellas (Astellas) company, male sex's castration tolerance in the late period prostate cancer spreading or recur is used for the treatment of in approval in Nikkei FDA (Food and Drug Adminstration) August 31 in 2012 (FDA), commodity are called Xtandi, and this medicine is oral preparations.Grace is mixed the Chinese chemical name of Shandong amine: 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-; English language Chemical title: 4-{3-[4-cyano-3-(triflutrifluoromethyl) phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-flu oro-N-methylbenzamide; Molecular formula: C
21h
16f
4n
4o
2s; Molecular weight: 464.44; CAS registration number: 915087-33-1.Grace Shandong amine of mixing is androgen receptor inhibitor, can suppress the combination of male sex hormone and acceptor competitively, and can suppress the nuclear translocation of androgen receptor and the interaction of this receptor and DNA.Experiment in vitro research display, grace Shandong amine of mixing can suppress the propagation of prostate cancer cell and induce it dead, and in the heteroplastic model experiment of Prostate Carcinoma of Mice, grace Shandong amine of mixing can reduce gross tumor volume.The mix major metabolite of Shandong amine of grace is that N-demethyl grace is mixed Shandong amine, and it shows the similar inhibit activities of Shandong amine of mixing to grace in vitro.The adult human dose that this medicine is recommended is 160mg every day, and absorb rapidly after taking medicine, plasma concentration reaches highest level in 0.5 ~ 3h, and the mean terminal transformation period is 5 ~ 8d, and main metabolic enzyme is CYP
2c
8and CYP
3a
4.This medicine should be avoided and strong CYP
2c
8inhibitor (as gemfibrozil, gemfibrozil) conbined usage.As needs co-administered, grace should be reduced and mix Shandong amine dosage to 80mg, every day 1 time.The mix common adverse reactions of Shandong amine of grace is weak, tired, and other common untoward reactions also comprise: backache, diarrhoea, arthrodynia, hectic fever, peripheral blood oedema, musculoskeletal pain, headache, anxiety and hypertension etc.
The grace of bibliographical information mix the synthetic route of Shandong amine be with the fluoro-4-brombenzamide of N-methyl-2-for starting raw material, be substituted, esterification, be obtained by reacting target compound with 3-trifluoromethyl-4-cyano-phenyl lsothiocyanates again.Synthetic route is as follows:
To mix Shandong amine synthesis fragment (chinesization formal name used at school: the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene) about grace, its preparation method only has report in patent CN200680025545, and method is as follows:
A kind of synthetic method of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene, with 4-amino-2-trifluoromethylbenzonitrile raw material, water is as solvent, 4-amino-2-trifluoromethylbenzonitrile is dropped to and stirs in the heterogeneous mixture of good thiophosgene in water, be obtained by reacting the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene, yield 92%;
Reaction equation is as follows:
There are the following problems for the method that the document provides:
1, thiophosgene is a kind of volatile liquid of severe toxicity, purchases and stores more inconvenient, dangerous;
2, experimental implementation is more dangerous;
3, test the hazard ratio of environment comparatively large, be unfavorable for large production.
In view of this; present inventor combines and is engaged in the chemical field particularly different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene research work experience for many years; study for a long period of time to the defect of above-mentioned technical field, technical scheme produces thus.
Summary of the invention
The object of the present invention is to provide the preparation method of the different Thiocyanato of a kind of 4--2-(trifluoromethyl) cyanobenzene, this preparation method is simple to operate, and security is high, and production cost is low, is suitable for suitability for industrialized production.
In order to better overcome prior art Problems existing, the technical solution used in the present invention is as follows:
The preparation method of the different Thiocyanato of a kind of 4--2-(trifluoromethyl) cyanobenzene, comprises the steps:
(1) (the 4-amino-2-trifluoromethylbenzonitrile shown in formula (I)) and triethylene diamine, dithiocarbonic anhydride are obtained by reacting compound (II);
(2) compound (II) and BTC are obtained by reacting the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene shown in formula (III);
Reaction formula is as follows:
Further, the molar ratio of described 4-amino-2-trifluoromethylbenzonitrile, triethylene diamine, dithiocarbonic anhydride is 1:3.0 ~ 5.0:3.0 ~ 5.0, preferred 1:4.0 ~ 5.0:4.0 ~ 5.0.
Further, described step (1) is specifically according to carrying out as follows: 4-amino-2-trifluoromethylbenzonitrile and triethylene diamine organic solvent A are dissolved, be cooled to-15 DEG C ~ 10 DEG C, dithiocarbonic anhydride is slowly added dropwise in reaction solution, control temperature is below 10 DEG C, fully react in room temperature after dropwising, reaction mixture obtains compound (II) through aftertreatment.
Further, described organic solvent A is selected from following a kind of or several arbitrarily combination: dioxane, tetrahydrofuran (THF), acetone, toluene, acetonitrile, methylene dichloride, most preferably toluene.
Further, 4-amino-2-trifluoromethylbenzonitrile and triethylene diamine organic solvent A are cooled to-5 DEG C ~ 5 DEG C after dissolving.
Further, in step (1), the room temperature reaction time is 12 ~ 24h, is preferably 16 ~ 24h.
Further, the molar ratio of described compound (II), BTC is 1:0.3 ~ 1.0, preferred 1:0.3 ~ 0.5.
Further; described step (2) is specifically according to carrying out as follows: dissolved by organic solvent B by compound (II); be cooled to-15 DEG C ~ 10 DEG C; the BTC solution dissolved by organic solvent B is dripped in reaction solution; control temperature is below 10 DEG C; fully react in room temperature after dropwising, gained reaction mixture obtains the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene through aftertreatment.
Further, described organic solvent B is selected from following a kind of or several arbitrarily combination: methylene dichloride, chloroform, tetracol phenixin, preferred chloroform.
Further, compound (II) is preferably cooled to-5 DEG C ~ 5 DEG C, is more preferably cooled to-5 DEG C ~ 0 DEG C after dissolving by organic solvent B.
Further, in step (2), the room temperature reaction time is 1 ~ 12h, preferably 1 ~ 3h.
Compared with prior art, beneficial effect of the present invention is: preparation method of the present invention is simple to operate, and security is high, and reaction yield is high, and production cost is low, is suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrogram of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene obtained in embodiment one.
Embodiment
Below in conjunction with accompanying drawing to enforcement further detailed description of the present invention, but protection scope of the present invention is not limited thereto:
Embodiment one
The preparation of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene
By 4-amino-2-trifluoromethylbenzonitrile (Compound I) (5.00g, 26.88mmol, 1.0eq) with triethylene diamine (9.03g, 80.65mmol, 3.0eq) dissolve with toluene (50ml), reaction solution is cooled to 0 DEG C, in reaction solution, slowly drips dithiocarbonic anhydride (6.13g, 80.65mmol, 3.0eq), reaction solution stirs 24h, has a large amount of yellow solid to separate out, by reacting liquid filtering, the a small amount of toluene drip washing of filter cake, dry, obtain yellow pressed powder, namely obtain chemical combination II;
After compound 2 is dissolved with chloroform (50ml); reaction solution is cooled to 0 DEG C; BTC (2.69g is dripped in reaction solution; 8.96mmol; chloroform (10ml) solution 0.33eq); keep reacting liquid temperature below 5 DEG C; after dripping; recover room temperature reaction 2h; after in reaction solution, insolubles filters out; filtrate is concentrated obtains crude product, crude product sherwood oil: ethyl acetate (2:1) column chromatography obtains the different Thiocyanato of faint yellow solid 4--2-(trifluoromethyl) cyanobenzene (3.58g, 58.4%).
EI-MS[M+1]＝229.1；
1HNMR(500MHz,CDCl3).84(d,J＝8.3Hz,1H),7.58(d,J＝1.7Hz,1H),7.49(dd,J＝8.3,1.8Hz,1H)。
Embodiment two
The preparation of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene
By 4-amino-2-trifluoromethylbenzonitrile (Compound I) (5.00g, 26.88mmol, 1.0eq) with triethylene diamine (9.03g, 107.52mmol, 4.0eq) dissolve with toluene (50ml), reaction solution is cooled to 0 DEG C, in reaction solution, slowly drips dithiocarbonic anhydride (6.13g, 107.52mmol, 4.0eq), reaction solution stirs 24h, has a large amount of yellow solid to separate out, by reacting liquid filtering, the a small amount of toluene drip washing of filter cake, dry, obtain yellow pressed powder, namely obtain Compound II per;
After compound 2 is dissolved with chloroform (50ml); reaction solution is cooled to 0 DEG C; BTC (3.20g is dripped in reaction solution; 10.75mmol; chloroformic solution (10ml) 0.4eq); keep reacting liquid temperature below 5 DEG C; after dripping; recover room temperature reaction 2h; after in reaction solution, insolubles filters out; filtrate is concentrated obtains crude product, crude product sherwood oil: ethyl acetate (2:1) column chromatography obtains the different Thiocyanato of faint yellow solid 4--2-(trifluoromethyl) cyanobenzene (5.24g, 85.5%).
Embodiment three
The preparation of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene
By 4-amino-2-trifluoromethylbenzonitrile (Compound I) (5.00g, 26.88mmol, 1.0eq) with triethylene diamine (15.05g, 134.40mmol, 5.0eq) dissolve with toluene (50ml), reaction solution is cooled to 0 DEG C, in reaction solution, slowly drips dithiocarbonic anhydride (10.21g, 134.40mmol, 5.0eq), reaction solution stirs 24h, has a large amount of yellow solid to separate out, by reacting liquid filtering, the a small amount of toluene drip washing of filter cake, dry, obtain yellow pressed powder, namely obtain Compound II per;
After Compound II per is dissolved with chloroform (50ml); reaction solution is cooled to 0 DEG C; BTC (4.03g is dripped in reaction solution; 13.44mmol; chloroformic solution 0.50eq); keep reacting liquid temperature below 5 DEG C; after dripping; recover room temperature reaction 2h; after in reaction solution, insolubles filters out; filtrate is concentrated obtains crude product, crude product sherwood oil: ethyl acetate (2:1) column chromatography obtains the different Thiocyanato of faint yellow solid 4--2-(trifluoromethyl) cyanobenzene (5.13g, 83.7%).
Embodiment four
The preparation of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene
By 4-amino-2-trifluoromethylbenzonitrile (Compound I) (5.00g, 26.88mmol, 1.0eq) with triethylene diamine (9.03g, 80.65mmol, 3.0eq) dissolve with toluene (50ml), reaction solution is cooled to 0 DEG C, in reaction solution, slowly drips dithiocarbonic anhydride (6.13g, 80.65mmol, 3.0eq), reaction solution stirs 24h, has a large amount of yellow solid to separate out, by reacting liquid filtering, the a small amount of toluene drip washing of filter cake, dry, obtain yellow pressed powder, namely obtain Compound II per;
After Compound II per is dissolved with chloroform (50ml); reaction solution is cooled to 0 DEG C; BTC (4.03g is dripped in reaction solution; 13.44mmol; chloroform (10ml) solution 0.50eq); keep reacting liquid temperature below 5 DEG C; after dripping; recover room temperature reaction 2h; after in reaction solution, insolubles filters out; filtrate is concentrated obtains crude product, crude product sherwood oil: ethyl acetate (2:1) column chromatography obtains the different Thiocyanato of faint yellow solid 4--2-(trifluoromethyl) cyanobenzene (4.56g, 74.4%).
Embodiment five
The preparation of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene
By 4-amino-2-trifluoromethylbenzonitrile (Compound I) (5.00g, 26.88mmol, 1.0eq) with triethylene diamine (9.03g, 80.65mmol, 3.0eq) dissolve with toluene (50ml), reaction solution is cooled to 0 DEG C, in reaction solution, slowly drips dithiocarbonic anhydride (6.13g, 80.65mmol, 3.0eq), reaction solution stirs 24h, has a large amount of yellow solid to separate out, by reacting liquid filtering, the a small amount of toluene drip washing of filter cake, dry, obtain yellow pressed powder, namely obtain chemical combination II;
After compound 2 is dissolved with chloroform (50ml); reaction solution is cooled to-5 DEG C; BTC (2.69g is dripped in reaction solution; 8.96mmol; chloroform (10ml) solution 0.33eq); keep reacting liquid temperature below 0 DEG C; after dripping; recover room temperature reaction 2h; after in reaction solution, insolubles filters out; filtrate is concentrated obtains crude product, crude product sherwood oil: ethyl acetate (2:1) column chromatography obtains the different Thiocyanato of faint yellow solid 4--2-(trifluoromethyl) cyanobenzene (4.88g, 79.6%).
Embodiment six
The preparation of the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene
By 4-amino-2-trifluoromethylbenzonitrile (Compound I) (5.00g, 26.88mmol, 1.0eq) with triethylene diamine (9.03g, 107.52mmol, 4.0eq) dissolve with toluene (50ml), reaction solution is cooled to 5 DEG C, in reaction solution, slowly drips dithiocarbonic anhydride (6.13g, 107.52mmol, 4.0eq), reaction solution stirs 24h, has a large amount of yellow solid to separate out, by reacting liquid filtering, the a small amount of toluene drip washing of filter cake, dry, obtain yellow pressed powder, namely obtain Compound II per;
After compound 2 is dissolved with chloroform (50ml); reaction solution is cooled to-5 DEG C; BTC (3.20g is dripped in reaction solution; 10.75mmol; chloroformic solution (10ml) 0.4eq); keep reacting liquid temperature below 0 DEG C; after dripping; recover room temperature reaction 2h; after in reaction solution, insolubles filters out; filtrate is concentrated obtains crude product, crude product sherwood oil: ethyl acetate (2:1) column chromatography obtains the different Thiocyanato of faint yellow solid 4--2-(trifluoromethyl) cyanobenzene (5.42g, 88.4%).
Claims (9)
1. a preparation method for the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene, comprises the steps:
(1) the 4-amino-2-trifluoromethylbenzonitrile shown in formula (I) and triethylene diamine, dithiocarbonic anhydride are obtained by reacting compound (II);
(2) compound (II) and BTC are obtained by reacting the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene shown in formula (III); Reaction formula is as follows:
2. preparation method as claimed in claim 1, it is characterized in that: in step (1), the molar ratio of described 4-amino-2-trifluoromethylbenzonitrile, triethylene diamine, dithiocarbonic anhydride is 1:3.0 ~ 5.0:3.0 ~ 5.0; In step (2), the molar ratio of described compound (II), BTC is 1:0.3 ~ 1.0.
3. preparation method as claimed in claim 1, it is characterized in that: in step (1), the molar ratio of described 4-amino-2-trifluoromethylbenzonitrile, triethylene diamine, dithiocarbonic anhydride is 1:4.0 ~ 5.0:4.0 ~ 5.0, in step (2), the molar ratio of described compound (II), BTC is 1:0.3 ~ 0.5.
4. the preparation method as described in one of claims 1 to 3, is characterized in that described preparation method carries out in accordance with the following steps:
(1) 4-amino-2-trifluoromethylbenzonitrile and triethylene diamine organic solvent A are dissolved, be cooled to-15 DEG C ~ 10 DEG C, dithiocarbonic anhydride is slowly added dropwise in reaction solution, control temperature is below 10 DEG C, fully react in room temperature after dropwising, reaction mixture obtains compound (II) through aftertreatment;
(2) compound (II) is dissolved by organic solvent B; be cooled to-15 DEG C ~ 10 DEG C; the BTC solution dissolved by organic solvent B is dripped in reaction solution; control temperature is below 10 DEG C; fully react in room temperature after dropwising, gained reaction mixture obtains the different Thiocyanato of 4--2-(trifluoromethyl) cyanobenzene through aftertreatment.
5. preparation method as claimed in claim 4, is characterized in that:
In step (1), described organic solvent A is selected from following a kind of or several arbitrarily combination: dioxane, tetrahydrofuran (THF), acetone, toluene, acetonitrile, methylene dichloride;
In step (2), described solvent B is selected from following a kind of or several arbitrarily combination: methylene dichloride, chloroform, tetracol phenixin.
6. preparation method as claimed in claim 5, it is characterized in that: in step (1), described solvent orange 2 A is toluene.
7. preparation method as claimed in claim 5, it is characterized in that: in step (2), described solvent B is chloroform.
8. preparation method as claimed in claim 4, is characterized in that: in step (1), and 4-amino-2-trifluoromethylbenzonitrile and triethylene diamine organic solvent A are cooled to-5 DEG C ~ 5 DEG C after dissolving; The room temperature reaction time is 12 ~ 24h.
9. preparation method as claimed in claim 4, is characterized in that: in step (2), and compound (II) is cooled to-5 DEG C ~ 5 DEG C after dissolving by organic solvent B; The room temperature reaction time is 1 ~ 12h.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108191727A (en) * | 2018-01-10 | 2018-06-22 | 山东铂源药业有限公司 | A kind of synthetic method of the different Thiocyanato -2- of 4- (trifluoromethyl) benzonitrile |
| CN109574895A (en) * | 2018-12-24 | 2019-04-05 | 常州智超化学有限公司 | A kind of 3- trifluoromethyl -4- cyano thiocyanic acid phenyl ester synthetic method |
| WO2019106691A1 (en) | 2017-11-28 | 2019-06-06 | Aarti Industries Limited | Process for preparation of enzalutamide using novel intermediate |
| CN110452166A (en) * | 2019-09-06 | 2019-11-15 | 浙江朗华制药有限公司 | A kind of preparation method of the different sulphur cyanato -3- trifluoromethyl -2- cyanopyridine of 5- |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019106691A1 (en) | 2017-11-28 | 2019-06-06 | Aarti Industries Limited | Process for preparation of enzalutamide using novel intermediate |
| EP3717457A4 (en) * | 2017-11-28 | 2021-04-28 | Aarti Industries Limited | Process for preparation of enzalutamide using novel intermediate |
| CN108191727A (en) * | 2018-01-10 | 2018-06-22 | 山东铂源药业有限公司 | A kind of synthetic method of the different Thiocyanato -2- of 4- (trifluoromethyl) benzonitrile |
| CN108191727B (en) * | 2018-01-10 | 2019-06-21 | 山东铂源药业有限公司 | A kind of synthetic method of the different Thiocyanato -2- of 4- (trifluoromethyl) benzonitrile |
| CN109574895A (en) * | 2018-12-24 | 2019-04-05 | 常州智超化学有限公司 | A kind of 3- trifluoromethyl -4- cyano thiocyanic acid phenyl ester synthetic method |
| CN110452166A (en) * | 2019-09-06 | 2019-11-15 | 浙江朗华制药有限公司 | A kind of preparation method of the different sulphur cyanato -3- trifluoromethyl -2- cyanopyridine of 5- |
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