CN104529848A - A method for synthesizing 4-(4-cyclopropylnaphthalen-1-yl)-1H-1,2,4-triazole-5(4H)-thione - Google Patents
A method for synthesizing 4-(4-cyclopropylnaphthalen-1-yl)-1H-1,2,4-triazole-5(4H)-thione Download PDFInfo
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- CN104529848A CN104529848A CN201410626221.XA CN201410626221A CN104529848A CN 104529848 A CN104529848 A CN 104529848A CN 201410626221 A CN201410626221 A CN 201410626221A CN 104529848 A CN104529848 A CN 104529848A
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Abstract
The present invention discloses a method for synthesizing 4-(4-cyclopropylnaphthalen-1-yl)-1H-1,2,4-triazole-5(4H)-thione. The method includes the following steps: using 4-cyclopropyl-1-naphthylamine (formula A) as a starting reactant, reacting the formula A with carbon disulfide to generate 4-cyclopropyl-1-naphthylamino dithiocarbamate (formula B) under a organic alkaline condition, reacting the formula B with bis (trichloromethyl) carbonate (BTC) or acylating reagents like ethyl chloroformate and methyl chloroformate, etc. to generate 4-cyclopropyl-1-naphthylamino dithiocarbamate chloro-carbonic acid anhydride, conducting decomposition reaction to the resulting product without separation and purification to produce 4-cyclopropyl-1-naphthyl isothiocyanate. The method uses carbon disulfide instead of thiophosgene with greater toxicity, and provides simple process and stable reaction. Furthermore, raw materials are readily available, and industrialization is easy to be realized with a total recovery of more than 65%.
Description
Technical field
The present invention relates to a kind of synthetic method of known compound, relate to the synthetic method of a kind of 1-cyclopropyl-4-different sulphur cyanato naphthalene in particular.
Background technology
1-cyclopropyl-4-different sulphur cyanato naphthalene is the important intermediate of antigout drug Lesinurad; Lesinurad is the novel antigout drug of Ardea Biosciences Inc. of U.S. exploitation; Lesinurad(referenced patent US0197825 can be obtained very easily by 1-cyclopropyl-4-different sulphur cyanato naphthalene), reaction formula is as follows:
1-cyclopropyl-4-different sulphur cyanato naphthalene the preparation method of current report is also fewer; except the synthesis that patent US0197825 reports it, patent WO2009070740A2, US2010056464A1, WO2011085009A2 etc. also refer to the synthetic method of intermediate 1-cyclopropyl-4-different sulphur cyanato naphthalene in the building-up process of report antigout drug Lesinurad:
This route reacts with 4-cyclopropyl-naphthalidine and thiophosgene.Use thiophosgene in the method, thiophosgene is a kind of volatile liquid of severe toxicity, and it is produced, it is all inconvenient to store and transport and use, larger to the harm of environment; .
Chinese patent CN102040546A, from 4-cyclopropyl-1 naphthaldehyde, has synthesized 1-cyclopropyl-4-different sulphur cyanato naphthalene through three-step reaction:
This route avoids the use of thiophosgene, but the method substantially prolongs the synthetic route of 1-cyclopropyl-4-different sulphur cyanato naphthalene, and make technique more complicated, cost is higher.
Summary of the invention
The present invention aims to provide a kind of new synthetic method preparing the intermediate 1-cyclopropyl-4-different sulphur cyanato naphthalene of antigout drug Lesinurad, and technical problem to be solved selects new operational path.
This operational path with 4-cyclopropyl-naphthalidine for starting raw material; first react in the basic conditions with dithiocarbonic anhydride and generate 4-cyclopropyl-naphthalidine base dithio formate; then with two (trichloromethyl) carbonic ether (triphosgene; BTC) or the acylting agent such as Vinyl chloroformate, methyl-chloroformate obtain 4-cyclopropyl-naphthalidine base dithiocarbonic acid chloromethane acid anhydrides through acylation reaction, obtain 1-cyclopropyl-4-different sulphur cyanato naphthalene after thermal degradation.The type reaction flow process of this process is as follows:
Preferably, the aprotic solvent reacted with dithiocarbonic anhydride can be benzene,toluene,xylene, and what select in the present patent application is toluene;
Preferably, organic basic condition can be provided by triethylamine, triethylene diamine or pyridine, and what select in the present patent application is triethylene diamine;
Preferably, 4-cyclopropyl-naphthalidine and dithiocarbonic anhydride react mol ratio be the mol ratio of the organic bases such as 1:2.5 ~ 1:3,4-cyclopropyl-naphthalidine and triethylene diamine, triethylamine, pyridine is 1:3 ~ 1:4;
Preferably; during preparation 1-cyclopropyl-4-different sulphur cyanato naphthalene (formula I), 4-cyclopropyl-naphthalidine base dithio formate can be selected to react with Vinyl chloroformate, methyl-chloroformate or BTC; select in the present patent application be BTC, 4-cyclopropyl-naphthalidine base dithio formate and BTC react mol ratio be 3:1.If when selecting Vinyl chloroformate, methyl-chloroformate to be acylting agent, the mol ratio of the reaction of described 4-cyclopropyl-naphthalidine base dithio formate and acylting agent is 1:1;
Preferably, during preparation 1-cyclopropyl-4-different sulphur cyanato naphthalene (formula I), the solvent that the acylting agents such as 4-cyclopropyl-naphthalidine base dithio formate (formula B) and BTC, methyl-chloroformate, Vinyl chloroformate react can be chloroform, methylene dichloride etc., and what select in the present patent application is chloroform;
Preferably, during preparation 1-cyclopropyl-4-different sulphur cyanato naphthalene (formula I), the charging process of the acylting agents such as BTC, methyl-chloroformate, Vinyl chloroformate takes reaction solvent to dissolve the mode slowly dripped to carry out, and it is 5 ~ 10 DEG C that dropping temperature controls;
Preferably, during preparation 1-cyclopropyl-4-different sulphur cyanato naphthalene (formula I), the temperature that the acylting agents such as 4-cyclopropyl-naphthalidine base dithio formate (formula B) and BTC, methyl-chloroformate, Vinyl chloroformate react is 40 ~ 65 DEG C.
The beneficial effect of employing technique scheme is:
(1) compared with thiophosgene method, with dithiocarbonic anhydride, BTC for reaction raw materials, toxicity comparatively low reaction process is simple, and the easy control security of reacting balance is higher; Thiophosgene raw material not easily obtains in addition, transport difficult, and dithiocarbonic anhydride, triphosgene are the industrial chemicals of ample supply of goods, and this makes cost greatly reduce;
(2) reaction raw materials wide material sources, 4-cyclopropyl-naphthalidine, dithiocarbonic anhydride, BTC can buy from market;
(3) 4-cyclopropyl-naphthalidine base dithio formate and BTC acylation reaction product 4-cyclopropyl-naphthalidine base dithiocarbonic acid chloromethane acid anhydrides are without being separated, and in reaction solution, 40 ~ 65 DEG C of thermal degradation obtain target product.Avoid material waste and additional process operations that separation brings, greatly reduce cost;
(4) with 4-cyclopropyl-phenyl formaldehyde be starting raw material the former technique of synthesis compared with; BTC acylation reaction is prepared 4-cyclopropyl-naphthalidine base dithiocarbonic acid chloromethane acid anhydrides and decomposition and is obtained target product one step and carry out; decrease operation step; avoid bromide reagents such as utilizing NBS simultaneously; improve the atom utilization of chemical reaction, decrease the generation of three industrial wastes.
Embodiment
Below technical scheme of the present invention is described, so that those skilled in the art understand.
Embodiment one:
In 250mL there-necked flask, add 100mL toluene, 18.3 g(0.100 mol) 4-cyclopropyl-naphthalidine, 33.7 g(0.3mol) triethylene diamine, stirred at ambient temperature.Drip dithiocarbonic anhydride 22.8g(0.300mol), add rear stirred at ambient temperature 4-10 hour, have a large amount of solid to separate out.Suction filtration, after drying, obtains 4-cyclopropyl-naphthalidine base dithiocarbonic acid triethylene diamine salt 33.5g, yield 90.1%;
Previous step is reacted solid product 33.5g(0.090 mol) add in 250mL tri-flasks, add 100mL chloroform, stirring cools to 5 ~ 10 DEG C, slow dropping is dissolved with BTC 9.9 g(0.033mol) chloroformic solution, finish rear stirring at room temperature and react 1 hour, after reaction terminates, be warmed up to 40 ~ 65 DEG C of back flow reaction 1 hour.Be cooled to room temperature, suction filtration removing insolubles, by reaction solution distillation except desolventizing obtains pale yellow oil 1-cyclopropyl-4-different sulphur cyanato naphthalene 16.0g, yield 78.8%.
Embodiment two:
In 250mL there-necked flask, add 100mL dimethylbenzene, 18.3 g(0.100 mol) 4-cyclopropyl-naphthalidine, 30.4 g(0.300mol) triethylamine, stirred at ambient temperature.Drip dithiocarbonic anhydride 22.8g(0.300 mol), add rear stirred at ambient temperature 4-10 hour, have a large amount of solid to separate out.Suction filtration, after drying, obtains 4-cyclopropyl-naphthalidine base dithiocarbonic acid triethylamine salt 31.8g, yield 88.2%;
Previous step is reacted solid product 31.8g(0.088 mol) add in 250mL tri-flasks, add 100mL methylene dichloride, stirring cools to 5 ~ 10 DEG C, slow dropping is dissolved with BTC 9.9 g(0.033mol) chloroformic solution, finish rear stirring at room temperature and react 1 hour, after reaction terminates, be warmed up to 40 ~ 65 DEG C of back flow reaction 3 hours.Be cooled to room temperature, suction filtration removing insolubles, by reaction solution distillation except desolventizing obtains pale yellow oil 1-cyclopropyl-4-different sulphur cyanato naphthalene 15.3g, yield 75.4%.
Embodiment three:
In 250mL there-necked flask, add 100mL dimethylbenzene, 18.3 g(0.100 mol) 4-cyclopropyl-naphthalidine, 23.7 g(0.300mol) pyridine, stirred at ambient temperature.Drip dithiocarbonic anhydride 22.8g(0.300 mol), add rear stirred at ambient temperature 4-10 hour, have a large amount of solid to separate out.Suction filtration, after drying, obtains 4-cyclopropyl-naphthalidine base dithiocarbonic acid pyridinium salt 29.5g, yield 87.1%;
Previous step is reacted solid product 29.5g(0.087 mol) add in 250mL tri-flasks, add 100mL chloroform, stirring cools to 5 ~ 10 DEG C, slow dropping is dissolved with Vinyl chloroformate 9.8 g(0.090mol) dichloromethane solution, finish rear stirring at room temperature and react 1 hour, after reaction terminates, be warmed up to 40 ~ 65 DEG C of back flow reaction 3 hours.Be cooled to room temperature, suction filtration removing insolubles, by reaction solution distillation except desolventizing obtains pale yellow oil 1-cyclopropyl-4-different sulphur cyanato naphthalene 15.5g, yield 76.2%.
As can be seen from above-mentioned three embodiments; the method of the present patent application is adopted to prepare the yield of 1-cyclopropyl-4-different sulphur cyanato naphthalene all more than 65%; and reaction process ratio faster; reaction environment and the relatively good control of temperature; the low poison solvent such as dithiocarbonic anhydride, BTC is adopted to replace the thiophosgene that toxicity is larger, easy to operate, little to environmental influence; security is high, and quality and the yield of the product of gained are all greatly improved.
Above-mentioned invention to be exemplarily described; obvious specific implementation of the present invention is not subject to the restrictions described above; as long as have employed this insubstantial that method of the present invention is conceived and technical scheme is carried out to improve; or the design of invention and technical scheme directly applied to other occasions, all within protection scope of the present invention without to improve.
Claims (7)
1. the synthetic method of a 1-cyclopropyl-4-different sulphur cyanato naphthalene, with 4-cyclopropyl-naphthalidine (formula A) for initial reactant, it is characterized by: at triethylene diamine, triethylamine, under the organic basic conditions such as pyridine, at toluene, in the benzene series organic solvents such as dimethylbenzene, 4-cyclopropyl-naphthalidine and dithiocarbonic anhydride react and generate 4-cyclopropyl-naphthalidine base dithio formate (formula B), again by 4-cyclopropyl-naphthalidine base dithio formate and two (trichloromethyl) carbonic ether (triphosgene, or Vinyl chloroformate BTC), 4-cyclopropyl-naphthalidine base dithiocarbonic acid chloromethane acid anhydrides that the acylting agent reactions such as methyl-chloroformate generate obtains 1-cyclopropyl-4-different sulphur cyanato naphthalene (formula I) through decomposition reaction,
(formula A)
(formula B)
(formula I).
2. the preparation method of a kind of 1-cyclopropyl-4-according to claim 1 different sulphur cyanato naphthalene, is characterized in that: described aprotic solvent can be the homologues such as dimethylbenzene, toluene or benzene.
3. the preparation method of 1-cyclopropyl-4-according to claim 1 different sulphur cyanato naphthalene, is characterized in that: described alkaline condition can be provided by organic basess such as triethylene diamine, triethylamine, pyridines.
4. the preparation method of 1-cyclopropyl-4-according to claim 1 different sulphur cyanato naphthalene; it is characterized in that: it be the mol ratio of the organic bases such as 1:2.5 ~ 1:3,4-cyclopropyl-naphthalidine and triethylene diamine, triethylamine, pyridine is 1:3 ~ 1:4 that 4-cyclopropyl-naphthalidine and dithiocarbonic anhydride react mol ratio.
5. the preparation method of a kind of 1-cyclopropyl-4-according to claim 1 different sulphur cyanato naphthalene, is characterized in that: the solvent that 4-cyclopropyl-naphthalidine base dithio formate and BTC react can be chloroform, methylene dichloride etc.
6. the preparation method of a kind of 1-cyclopropyl-4-according to claim 1 different sulphur cyanato naphthalene; it is characterized in that: BTC is by being added drop-wise in reaction system after dissolution with solvents; dropping temperature controls at 5-10 DEG C, and drip after terminating, temperature of reaction controls at 40 ~ 65 DEG C.
7. the preparation method of a kind of 1-cyclopropyl-4-according to claim 1 different sulphur cyanato naphthalene, is characterized in that: when being acylting agent when selecting BTC, the mol ratio that described 4-cyclopropyl-naphthalidine base dithio formate and BTC react is 3:1; When being acylting agent when selecting Vinyl chloroformate, methyl-chloroformate, the mol ratio of the reaction of described 4-cyclopropyl-naphthalidine base dithio formate and acylting agent is 1:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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- |
| WO2021249468A1 (en) * | 2020-06-11 | 2021-12-16 | 南京明德新药研发有限公司 | Preparation method for chlorinated compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759614A (en) * | 2008-12-26 | 2010-06-30 | 华东理工大学 | Preparation method of isothiocyanate |
| CN102643241A (en) * | 2007-11-27 | 2012-08-22 | 亚德生化公司 | Compounds and compositions and methods of use |
-
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- 2014-11-10 CN CN201410626221.XA patent/CN104529848A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643241A (en) * | 2007-11-27 | 2012-08-22 | 亚德生化公司 | Compounds and compositions and methods of use |
| CN101759614A (en) * | 2008-12-26 | 2010-06-30 | 华东理工大学 | Preparation method of isothiocyanate |
Non-Patent Citations (2)
| Title |
|---|
| 杜晓华，等: "非硫光气法合成一些难合成的芳基异硫氰酸酯", 《农药》, vol. 43, no. 2, 28 February 2004 (2004-02-28), pages 78 - 79 * |
| 梁学平: "异硫氰酸酯的合成研究进展", 《江西植保》, vol. 34, no. 3, 30 September 2011 (2011-09-30), pages 129 - 134 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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- |
| WO2021249468A1 (en) * | 2020-06-11 | 2021-12-16 | 南京明德新药研发有限公司 | Preparation method for chlorinated compound |
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