CN107400073A - A kind of 4 isothiocyanos 2（Trifluoromethyl）The synthetic method of benzonitrile - Google Patents
A kind of 4 isothiocyanos 2（Trifluoromethyl）The synthetic method of benzonitrile Download PDFInfo
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- CN107400073A CN107400073A CN201710771551.1A CN201710771551A CN107400073A CN 107400073 A CN107400073 A CN 107400073A CN 201710771551 A CN201710771551 A CN 201710771551A CN 107400073 A CN107400073 A CN 107400073A
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- trifluoromethyl
- isothiocyanos
- synthetic method
- benzonitrile
- cyano
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C333/02—Monothiocarbamic acids; Derivatives thereof
- C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
Abstract
The invention discloses a kind of synthetic method of 4 isothiocyano 2 (trifluoromethyl) benzonitriles, this method is divided into following two step：Step 1, with the cyano-aniline of 3 trifluoromethyl 4 (I) for initiation material, reacted with thio phenyl chloroformate in the organic solvents such as dichloromethane and obtain intermediate (II)；Step 2, intermediate (II) slough a molecule phenol in reflux in toluene reaction and obtain formula (III) product 4 isothiocyano 2 (trifluoromethyl) benzonitrile, and reaction equation is as follows：
Description
Technical field
The present invention relates to medicine intermediate synthesis technical field, and in particular to a kind of miscellaneous Shandong amine of anti-prostate cancer medicine grace is crucial
The synthetic method of intermediate 4- isothiocyanos -2- (trifluoromethyl) benzonitrile.
Background technology
4- isothiocyanos -2- (trifluoromethyl) benzonitrile belongs to isosulfocyanate compound, is synthesis anti-prostate cancer
The key intermediate of the miscellaneous Shandong amine of medicine grace.Its chemical synthesis typically using 3- trifluoromethyl -4- cyano-anilines as starting point raw material, due to containing
There is the strong electron-withdrawing group such as trifluoromethyl, cyano group group, inertia causes more by force the difficulty for synthesizing target product higher.At present, document has been
The synthetic method of report mainly has following three kinds.
Method one：Sawyers, Jung etc. (referring to WO2006124118A1) are using 3- trifluoromethyl -4- cyano-anilines as original
Material, reacts to obtain 4- isothiocyanos -2- (trifluoromethyl) benzonitrile at ambient temperature with thiophosgene.This method, which has used, waves
Hair property poisonous reagent thiophosgene, the reagent is unstable, is extremely easy in decomposition and produces hypertoxic smog SO2, it is harmful, and finally give birth to
Into substantial amounts of Thiourea accessory substance, yield is influenceed.This method reaction equation is as follows：
Method two：Song Lijun (monarch Song Li, king's Yang, Li Zhiyu etc..Fine-chemical intermediate, 2012,42 (1):34-36.)
With Sun Yingying (referring to CN104710367A) etc. using 3- trifluoromethyl -4- cyano-anilines as raw material, hydrogen is added under nitrogen protection
Change sodium, carbon disulfide backflow 20h is added dropwise, purified through column chromatography by plumbi nitras aqueous solution desulfurization to obtain target product after reaction completely
4- isothiocyanos -2- (trifluoromethyl) benzonitrile.The method substitutes thiophosgene using carbon disulfide, but subsequent process uses plumbi nitras
Aqueous solution desulfurization, generate substantial amounts of vulcanized lead precipitation.Product is difficult to separate among being coated on precipitation, and cumbersome yield is low and right
Environment is harmful to.This method reaction equation is as follows：
Method three：This method (referring to CN104610111A) is using 2- trifluoromethyl -4- anthranilo nitriles as raw material, organic
Alkali --- generation intermediate 3- trifluoromethyl -4- cyano-phenyls are reacted in the presence of-triethylene diamine (DABCO) with carbon disulfide
Dithio formate, then slough a molecule H in the presence of double (trichloromethyl) carbonic esters (BTC) of desulfuration reagent2S obtains mesh
Mark product I, yield 83.7%.This method yield is higher, but raw materials used expensive, and post-processes purifying and use column chromatography,
It is not suitable for industrialized production.Its reaction equation is as follows：
In summary, the synthetic method of existing medicine intermediate 4- isothiocyanos -2- (trifluoromethyl) benzonitrile is present
Many deficiency and shortcoming, develop a kind of new more efficient, safer, higher yield synthetic method and seem particularly significant.
The content of the invention
It is an object of the invention to overcome existing medicine intermediate 4- isothiocyanos -2- (trifluoromethyl) benzonitrile synthesis work
A kind of variety of problems existing for skill, there is provided new synthetic method.This method is easy to operate, high income, will not use thiophosgene etc.
Poisonous and harmful substance, thus safer more meet environment-friendly requirement.
To achieve the above object, the technical solution adopted in the present invention is as follows：
A kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile, comprises the following steps：(a) with 3- trifluoros
Methyl -4- cyano-anilines and thio phenyl chloroformate are raw material, react and are obtained among thiocarbamate in organic solvent A
Body；(b) thiocarbamate intermediate flows back in organic solvent B sloughs phenol and obtains target product 4- isothiocyanos -2-
(trifluoromethyl) benzonitrile.
In such scheme, the organic solvent A is one kind in dichloromethane, tetrahydrofuran, chloroform, acetonitrile.
In such scheme, the organic solvent B is toluene.When using dichloromethane, chloroform, tetrahydrofuran, acetonitrile etc. as
When organic solvent B flows back, it cannot get target product 4- isothiocyanos -2- (trifluoromethyl) benzonitrile.
In such scheme, the molar ratio of raw material 3- trifluoromethyl -4- cyano-anilines and thio phenyl chloroformate is 1-
3:1。
Preferably, the molar ratio of raw material 3- trifluoromethyls -4- cyano-anilines and thio phenyl chloroformate is 2:1.
Further, the concentration of 3- trifluoromethyl -4- cyano-anilines is in mixed solution before being reacted in step (a)
0.3mol/L, the concentration of thiocarbamate intermediate is 0.1mol/L in solution before the middle backflow of step (b).
In such scheme, step (a) reaction temperature is 25 DEG C, reaction time 1-5h.
Preferably, step (a) reaction temperature is 25 DEG C, reaction time 2h.
In such scheme, step (b) reflux time is 8-24h.
Preferably, step (b) reflux time is 15-20h.
Compared with prior art, the beneficial effects of the present invention are：Reaction need not use the plays such as thiophosgene and carbon disulfide
Malicious reagent, without volume exogenously added alkali；The thio phenyl chloroformate of raw material used, cheap, environment-protecting clean, suitable for industrial metaplasia
Production, product yield is higher under preferred reaction conditions by contrast.
Brief description of the drawings
Fig. 1 is 4- isothiocyanos -2- (trifluoromethyl) benzonitrile prepared by the embodiment of the present invention 11H-NMR spectrum；
Fig. 2 is 4- isothiocyanos -2- (trifluoromethyl) benzonitrile HPLC spectrograms prepared by the embodiment of the present invention 2.
Embodiment
For a better understanding of the present invention, with reference to the embodiment content that the present invention is furture elucidated, but the present invention is not
It is limited only to the following examples.
A kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile, first with 3- trifluoromethyl -4- cyano group benzene
Amine (I) and thio phenyl chloroformate are raw material, in 25 DEG C of reactions in dichloromethane or tetrahydrofuran or chloroform or acetonitrile solvent
1-5 hours obtain intermediate product (II), and intermediate product is dissolved in into reflux in toluene 8-24h sloughs phenol, filtered concentration purification
After obtain target product (III), specific reaction equation is as follows：
Embodiment 1
The synthetic method of different sulphur cyanogen -2- (trifluoromethyl) benzonitriles of 4-, comprises the following steps：
A. by 3- trifluoromethyl -4- cyano-anilines (chemical compounds I) (1.12g, 6mmol, 1.0eq) and thio phenyl chloroformate
(1.04g, 6mmol, 1.0eq) is dissolved with 20mL dichloromethane, and 25 DEG C or so start to stir, and is reacted complete after 2h, is filtered, removes
Insoluble matter, collects filtrate, and removal of solvent under reduced pressure obtains yellow solid (II).
B. yellow solid (II) (0.64g, 2mmol) is weighed, is dissolved in 20mL toluene, heating stirring keeps 18h to flowing back
Afterwards.Insoluble matter in reaction solution is filtered out, filtrate is collected, is concentrated under reduced pressure to give crude product, it is different that target product 4- is obtained after column chromatography
Sulphur cyanogen -2- (trifluoromethyl) benzonitrile 274mg, yield 60.1%.
Different sulphur cyanogen -2- (trifluoromethyl) benzonitriles of target product 4- prepared to embodiment 1 are carried out1H-NMR is tested, knot
Fruit is as shown in figure 1, the ownership result of each peak position is as follows in Fig. 1：
Sample1The chemical shift of H-NMR data 8.29,7.92,8.03 demonstrates the structure of target product.
Embodiment 2
The synthetic method of different sulphur cyanogen -2- (trifluoromethyl) benzonitriles of 4-, comprises the following steps：
A. by 3- trifluoromethyl -4- cyano-anilines (chemical compounds I) (1.12g, 6mmol, 1.0eq) and thio phenyl chloroformate
(0.69g, 4mmol, 0.67eq) is dissolved with 20mL dichloromethane, and 25 DEG C or so start to stir, and is reacted complete after 2h, filtering, is removed
Insoluble matter is removed, collects filtrate, removal of solvent under reduced pressure obtains yellow solid (II).
B. yellow solid (II) (0.64g, 2mmol) is weighed, is dissolved in 20mL toluene, heating stirring keeps 18h to flowing back
Afterwards.Insoluble matter in reaction solution is filtered out, filtrate is collected, is concentrated under reduced pressure to give crude product, it is different that target product 4- is obtained after column chromatography
Sulphur cyanogen -2- (trifluoromethyl) benzonitrile 330mg, yield 72.3%.
Different sulphur cyanogen -2- (trifluoromethyl) benzonitriles of target product 4- prepared to embodiment 2 have carried out HPLC tests, as a result
As shown in Figure 2 and Table 1.Test condition：Agilent1100 type high performance liquid chromatographs, chromatographic column HypersiBDS-C18Chromatogram
Post (200 × 4.6mm, 5 μm), methanol-water (80:20) it is mobile phase, Detection wavelength 254nm, flow velocity 1.0mL/min, column temperature
25℃。
The gained sample HPLC assay result tables of 1 embodiment of table 2
Embodiment 3
The synthetic method of different sulphur cyanogen -2- (trifluoromethyl) benzonitriles of 4-, comprises the following steps：
A. by 3- trifluoromethyl -4- cyano-anilines (chemical compounds I) (1.12g, 6mmol, 1.0eq) and thio phenyl chloroformate
(0.52g, 3mmol, 0.52eq) is dissolved with 20mL dichloromethane, and 25 DEG C or so start to stir, and is reacted complete after 2h, filtering, is removed
Insoluble matter is removed, collects filtrate, removal of solvent under reduced pressure obtains yellow solid (II).
B. yellow solid (II) (0.64g, 2mmol) is weighed, is dissolved in 20mL toluene, heating stirring keeps 18h to flowing back
Afterwards.Insoluble matter in reaction solution is filtered out, filtrate is collected, is concentrated under reduced pressure to give crude product, it is different that target product 4- is obtained after column chromatography
Sulphur cyanogen -2- (trifluoromethyl) benzonitrile 361mg, yield 79.0%.
Embodiment 4
The synthetic method of different sulphur cyanogen -2- (trifluoromethyl) benzonitriles of 4-, comprises the following steps：
A. by 3- trifluoromethyl -4- cyano-anilines (chemical compounds I) (1.12g, 6mmol, 1.0eq) and thio phenyl chloroformate
(0.35g, 2mmol, 0.35eq) is dissolved with 20mL dichloromethane, and 25 DEG C or so start to stir, and is reacted complete after 2h, filtering, is removed
Insoluble matter is removed, collects filtrate, removal of solvent under reduced pressure obtains yellow solid (II).
B. yellow solid (II) (0.64g, 2mmol) is weighed, is dissolved in 20mL toluene, heating stirring keeps 18h to flowing back
Afterwards.Insoluble matter in reaction solution is filtered out, filtrate is collected, is concentrated under reduced pressure to give crude product, it is different that target product 4- is obtained after column chromatography
Sulphur cyanogen -2- (trifluoromethyl) benzonitrile 335mg, yield 73.5%.
Claims (10)
1. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile, it is characterised in that comprise the following steps：(a)
Using 3- trifluoromethyl -4- cyano-anilines and thio phenyl chloroformate as raw material, reacted in organic solvent A and obtain sulfo-amino first
Acid esters intermediate；(b) thiocarbamate intermediate flows back in organic solvent B sloughs phenol and obtains the different sulphur of target product 4-
Cyano group -2- (trifluoromethyl) benzonitrile.
2. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 1, its feature exist
In：The organic solvent A is one kind in dichloromethane, tetrahydrofuran, chloroform, acetonitrile.
3. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 1, its feature exist
In：The organic solvent B is toluene.
4. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 1, its feature exist
In：The molar ratio of raw material 3- trifluoromethyl -4- cyano-anilines and thio phenyl chloroformate is 1-3:1.
5. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 4, its feature exist
In：The molar ratio of raw material 3- trifluoromethyl -4- cyano-anilines and thio phenyl chloroformate is 2:1.
6. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 1, its feature exist
In：The concentration of 3- trifluoromethyl -4- cyano-anilines is 0.3mol/L in mixed solution before being reacted in step (a), is returned in step (b)
The concentration of thiocarbamate intermediate is 0.1mol/L in solution before stream.
7. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 1, its feature exist
In：Step (a) reaction temperature is 25 DEG C, reaction time 1-5h.
8. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 7, its feature exist
In：Step (a) reaction temperature is 25 DEG C, reaction time 2h.
9. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 1, its feature exist
In：Step (b) reflux time is 8-24h.
10. a kind of synthetic method of 4- isothiocyanos -2- (trifluoromethyl) benzonitrile according to claim 9, its feature
It is：Step (b) reflux time is 15-20h.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112876391A (en) * | 2021-01-15 | 2021-06-01 | 山东铂源药业有限公司 | Synthetic method of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile |
| CN113717086A (en) * | 2021-08-18 | 2021-11-30 | 江西金丰药业有限公司 | Preparation method of green and environment-friendly 4-isothiocyanato-2- (trifluoromethyl) benzonitrile |
| CN115181043A (en) * | 2022-07-27 | 2022-10-14 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 4-isothiocyanato-2- (trifluoromethyl) benzonitrile by continuous flow |
| CN115819303A (en) * | 2022-11-15 | 2023-03-21 | 江苏睿实生物科技有限公司 | Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112876391A (en) * | 2021-01-15 | 2021-06-01 | 山东铂源药业有限公司 | Synthetic method of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile |
| CN113717086A (en) * | 2021-08-18 | 2021-11-30 | 江西金丰药业有限公司 | Preparation method of green and environment-friendly 4-isothiocyanato-2- (trifluoromethyl) benzonitrile |
| CN113717086B (en) * | 2021-08-18 | 2023-03-10 | 江西金丰药业有限公司 | Preparation method of green and environment-friendly 4-isothiocyanato-2- (trifluoromethyl) benzonitrile |
| CN115181043A (en) * | 2022-07-27 | 2022-10-14 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 4-isothiocyanato-2- (trifluoromethyl) benzonitrile by continuous flow |
| CN115819303A (en) * | 2022-11-15 | 2023-03-21 | 江苏睿实生物科技有限公司 | Preparation method of compound 3-fluoro-4-isothiocyanato-2-trifluoromethyl benzonitrile |
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