CN107501209A

CN107501209A - The carboxylic acid tert-butyl ester synthetic method of 4 [2 (the bromobenzene sulfydryl of 2 methyl 4) phenyl] piperazine 1

Info

Publication number: CN107501209A
Application number: CN201610411179.9A
Authority: CN
Inventors: 刘俊; 刘伟; 张建海
Original assignee: Jiangsu Jibeier Pharmaceutical Co Ltd
Current assignee: Jiangsu Jibeier Pharmaceutical Co Ltd
Priority date: 2016-06-14
Filing date: 2016-06-14
Publication date: 2017-12-22

Abstract

The synthetic method for the carboxylic acid tert-butyl ester of important intermediate 4 [2 (the bromobenzene sulfydryl of 2 methyl 4) phenyl] piperazine 1 that may relate to the invention discloses deuterated Vortioxetine hydrobromate, it comprises the following steps：（1）Under 100 150 DEG C of heating conditions, the toluene bromide of 2 iodine 5 is with o-amino thiophenol through mantoquita and ligand catalysis reaction 2 (the bromobenzene sulfydryl of 2 methyl 4) aniline of generation；（2）Two（2 chloroethyls）Amine hydrochlorate double (2 chloroethyl) t-butyl carbamates of reaction generation N, N under alkali effect with Boc acid anhydrides；（3）2 (the bromobenzene sulfydryl of 2 methyl 4) aniline and double (2 chloroethyl) t-butyl carbamates of N, N react 1 [2 (the bromobenzene sulfydryl of 2 methyl 4) phenyl] piperazine of generation in diethylene glycol monomethyl ether.

Description

4- [2- (the bromo- benzene sulfydryls of 2- methyl -4-)-phenyl] piperazine -1- carboxylic acid tert-butyl esters synthesize Method

Technical field

The present invention relates to a kind of deuterated Vortioxetine hydrobromate intermediate 4- [2- (the bromo- benzene sulfydryls of 2- methyl -4-)-benzene Base] piperazine -1- carboxylic acid tert-butyl esters synthetic method, belong to chemical synthesis and technology field.

Background technology

Depression is a kind of mental illness, body function can be caused abnormal or even disabled, the illness rate of China's depression is big About 3%-5%, according to the prediction of the World Health Organization, to the year two thousand thirty, depression is likely to the main original for causing deformity Cause.

The symptom of depression can be emotional change and other symptoms, this direct interference people work, study, sleep, diet Deng daily life.The symptom of depression includes daily routines and loses interest, body weight significant change, sleep abnormality, sense of guilt, easy to be tired Labor, uneasiness, valueless sense, slowness of thinking, absent minded, even introgression etc., the symptom of certain patients with depression is simultaneously It is non-the same.

The occurrence cause of depression includes central norepinephrine（NE）, serotonin（5-HT）And dopamine（DA）Deng Monoamine god's neurotransmitter content is too low and its receptor hypo-function.Medicine currently used for treating depression mainly has three classes, One kind is standard care medicine-tricyclic antidepressant of depression（Tricyclic antidepressant, TCA）, this medicine The concentration of NE and 5-HT in brain can be improved, but is serious adverse reaction the shortcomings that its is maximum, such as cardiac toxic, and work very Slowly；Second class antidepressants are MAOI（Monoamine oxidaseinhibitor, MA0I）, it passes through Delay the degraded of NE and 5-HT in brain, antidepressant effect is played by extending the action time of these mediators.3rd class Antidepressants-selective 5-HT reuptaking inhibitors（Selective serotoninreuptake inhibitor, SSRI）, it can be by suppressing reuptake of the presynaptic membrane to 5-HT, to increase synaptic cleft 5-HT concentration, so as to improve The excitability of postsynaptic membrane 5-HT1A acceptors, is finally reached antidepressant effect.Its advantages of is not influence other neurotransmitters Acceptor, therefore relatively safety.But because SSRI non-selectively acts on the various hypotypes of 5-HT acceptors, therefore one can be caused A little corresponding adverse reactions.

Vortioxetine hydrobromate is the medicine for treating severe depression, in September, 2013 through U.S.'s food and medicine pipe Reason office（FDA）Approval listing, is by Denmark's Lundbeck pharmacy（Lundbeck）With the military field drug company of Japan（Takada Pharmaceutical）Cooperative research and development.Major depressive disorder is commonly known as depression, is a kind of mental illness, disease patient can go out Existing pessimistic and worldweary, desperate, illusion vain hope, poor appetite, even hypofunction, suicide.The work of one people of severe jamming, The normal activity of life, study and diet etc..The medicine is considered as by suppressing serotonin transporter, and to 5-HT Receptor subtype carries out Active Regulation and plays antidepressant effect.Find that deuterated Vortioxetine hydrobromate replaces than fertile by clinical test Western spit of fland hydrobromate is more effective in cure to severe treating depression.

The content of the invention

The technical problems to be solved by the invention are to provide a kind of Vortioxetine hydrobromate intermediate 4- [2- (2- first The bromo- benzene sulfydryls of base -4-)-phenyl] piperazine -1- carboxylic acid tert-butyl esters synthetic method, to solve the problems, such as that yield is low, the present invention adopts Technical scheme is as follows：

。

（1）The iodo- 5- toluene bromides (I) of 2- and near amino thiophenols (II) heat 100 ~ 150 DEG C in mantoquita and ligand catalysis, Reaction prepares 2- (the bromo- benzene sulfydryls of 2- methyl -4-) aniline (III)；

（2）Two (2- chloroethyls) amine hydrochlorates (IV) double (2- chloroethyls) ammonia of reaction generation N, N- under alkali effect with Boc acid anhydrides Base t-butyl formate (V)；

（3）2- (the bromo- benzene sulfydryls of-methyl -4-) aniline (III) and double (2- chloroethyls) t-butyl carbamates (V) of N, N- are two Glycol monoethyl ether heats 160 DEG C of reaction generation 1- [2-（The bromo- benzene sulfydryls of 2- methyl -4-）- phenyl] piperazine (VI).

Step（1）In, described catalyst is stannous chloride, cuprous bromide, preferably cuprous iodide, stannous chloride, iodate It is cuprous.

Step（1）In, described part is tetramethylethylenediamine, cyclohexanediamine, preferably 2,2'- bipyridyls, tetramethyl second Diamines, cyclohexanediamine.

Step（1）In, preferably 100 ~ 120 DEG C of described temperature.

Step（2）In, described alkali is triethylamine, diisopropylethylamine, tetramethylethylenediamine, preferably triethylamine, two different Propylethylamine.

Step（3）In, described solvent is diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, excellent Select diethylene glycol monoethyl ether, diethylene glycol monomethyl ether.

Step（3）In, preferably 140 ~ 160 DEG C of described temperature.

Compared with prior art, advantage is a kind of deuterated Vortioxetine hydrobromate intermediate 4- [2- (2- first to the present invention The bromo- benzene sulfydryls of base -4-)-phenyl] piperazine -1- carboxylic acid tert-butyl esters synthesis technique.

（1）Preparation method of the present invention, technique is simple, high income, is adapted to industrialized production.

（2）The product purification methods of the present invention are simple, and cost is low.

（3）The catalyst price that the present invention uses is low, substantially reduces production cost, and post-processes simply, avoids catalysis Toxic side effect caused by agent residual.

Embodiment

According to following embodiments, the present invention may be better understood.It is however, as it will be easily appreciated by one skilled in the art that real Apply the content described by example and be merely to illustrate the present invention, without should be also without limitation on sheet described in detail in claims Invention.

Embodiment 1：

Under argon gas protection, the iodo- 5- toluene bromides (I) of 100.0g 2-, 42.1g o-amino thiophenols are added into 500 mL there-necked flasks (II), 1.74 g stannous chlorides, 78.0 g tetramethylethylenediamines, stirring, oil bath heating react 6 h to 120 DEG C.Reaction solution is cold But 300 mL ethyl acetate are added to room temperature, and purify water washing with 30 mL*3 ammoniacal liquor, 100mL*3, then with 100ml saturations food Salt solution washed once, and with anhydrous sodium sulfate drying organic phase, be spin-dried for, and adds 100mL petroleum ethers, -0- is cooled under quick stirring 25 DEG C, and separated out with a large amount of solids, decompression is filtered, and filter cake is eluted with petroleum ether.Collect filter cake and be dried under reduced pressure at 40 DEG C Obtain 2- (the bromo- benzene sulfydryls of 2- methyl -4-) aniline (III) 85g, yield 85.8%.

Embodiment 2：

100g bis- (2- chloroethyls) amine hydrochlorate (IV) is added in 500 mL there-necked flasks and adds the dissolving of 300mL dichloromethane, 113g triethylamines are added, are stirred continuously lower dropwise addition 147gBoc acid anhydrides, react 4 ~ 6 h.Add 200 mL purified waters, liquid separation, 200 mL saturated common salt water washings are added, with anhydrous sodium sulfate drying, are spin-dried for, obtain double (2- chloroethyls) ammonia of grease N, N- Base t-butyl formate (V) 133g, yield 98%.

Embodiment 3：

80g 2- (the bromo- benzene sulfydryls of 2- methyl -4-) aniline (III), double (the 2- chlorine of 79 g N, N- are added in 500 mL there-necked flasks Ethyl) t-butyl carbamate (V), 240 mL diethylene glycol monoethyl ethers, magnetic agitation, 160 DEG C of oil bath, react 4 ~ 6 h.Will Reaction solution is cooled to room temperature, adds 300 mL purified waters, adds 300 mL methyl tertiary butyl ether(MTBE)s, stirs, and filters, and filter cake is used Methyl tertiary butyl ether(MTBE) stirs wash again, filters to obtain 1- [2- (the bromo- benzene sulfydryls of 2- methyl -4-)-phenyl] piperazine（Ⅴ）104.7 g, receive Rate 83.1%.

Claims

A kind of 1. deuterated Vortioxetine hydrobromate intermediate 4- [2- (the bromo- benzene sulfydryls of 2- methyl -4-)-phenyl] piperazine -1- carboxylics Tert-butyl acrylate synthesizes, including following operating procedure:

（1）The iodo- 5- toluene bromides (I) of 2- are reacted near amino thiophenols (II) under catalyst, ligand catalysis, and reaction temperature is 100 ~ 150 DEG C, reaction generation 2- (the bromo- benzene sulfydryls of 2- methyl -4-) aniline (III)；

（2）Two（2- chloroethyls）Amine hydrochlorate (IV) reacts generation N, N- couple (2- chloroethyls) in the basic conditions with Boc acid anhydrides T-butyl carbamate (V)；

（3）2- (the bromo- benzene sulfydryls of 2- methyl -4-) aniline (III) and double (2- chloroethyls) t-butyl carbamates (V) of N, N- are two Glycol monoethyl ether heats 160 DEG C of reaction generation 1- [2- (the bromo- benzene sulfydryls of 2- methyl -4-)-phenyl] piperazines (VI).
2. synthetic method according to claim 1, it is characterised in that step（1）Described in catalyst for stannous chloride, Cuprous bromide, cuprous iodide, preferably stannous chloride, cuprous iodide.
3. synthetic method according to claim 1, it is characterised in that step（1）Described in part be tetramethyl second two Amine, cyclohexanediamine, 2,2'- bipyridyls, preferably tetramethylethylenediamine, cyclohexanediamine.
4. synthetic method according to claim 1, it is characterised in that step（1）Described in temperature preferably 100 ~ 120 ℃。
5. synthetic method according to claim 1, it is characterised in that step（2）Described in alkali for triethylamine, diisopropyl Base ethamine, tetramethylethylenediamine, preferably triethylamine, diisopropylethylamine.
6. synthetic method according to claim 1, it is characterised in that step（3）Described in solvent be diethylene glycol list second Ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, preferably diethylene glycol monoethyl ether, diethylene glycol monomethyl ether.
7. synthetic method according to claim 1, it is characterised in that step（3）Described in temperature preferably 140 ~ 160 ℃。