CN106279071B - Phenylpiperazine derivatives and its application method and purposes - Google Patents

Phenylpiperazine derivatives and its application method and purposes Download PDF

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Publication number
CN106279071B
CN106279071B CN201610652904.1A CN201610652904A CN106279071B CN 106279071 B CN106279071 B CN 106279071B CN 201610652904 A CN201610652904 A CN 201610652904A CN 106279071 B CN106279071 B CN 106279071B
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piperazine
phenyl
compound
reaction
base
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CN106279071A (en
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金传飞
易超
张英俊
薛亚萍
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms

Abstract

The present invention relates to Phenylpiperazine derivatives and its application methods and purposes, specifically disclose a kind of for inhibiting the Phenylpiperazine derivatives and its pharmaceutical composition of serotonin reuptake transporter.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and their purposes in pivot nervous system dysfunction, the especially disturbance of emotion in the treatment.

Description

Phenylpiperazine derivatives and its application method and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for treating central nervous system dysfunction, especially feelings The compound and composition and its application method and purposes of sense obstacle.Particularly, of the present invention is that can be used as 5- hydroxyl color The Phenylpiperazine derivatives of amine reuptaking inhibitor.
Background technique
Serotonin (5-HT, serotonin), a kind of neurotransmitter for transmitting signal in brain and nervous system, In central nervous system (CNS) dysfunction, especially in anxiety, depression, invasion and impulsion mood, important angle play Color.Serotonin Transporter (5-HT transporter, 5-HTT/serotonin transporter, SERT) is a kind of right 5-HT has the transmembrane transporter of high affinity, it reuptakes serotonin from nerve synapse gap and enters presynaptic mind Through member, the concentration of synaptic cleft serotonin is directly affected.
In history, the drug therapy of the disturbance of emotion start from the 1950s, include tricyclic antidepressant (TCAs) and Monoamine oxidase inhibitors (MAOIs), these drugs are mainly by neurotransmitter (dopamine, norepinephrine and 5- hydroxyl color Amine) blocking effect play curative effect.However, the non-selective and undesirable side effect to target limits making for they With.To in the 1980s, selective serotonin reuptake inhibitor (selective serotonin reuptake Inhibitors, SSRIs) appearance, change this situation.Compared with TCAs, this kind of curative effect of medication is suitable, but side effect It is small, even if excessive use, also smaller (Sarko J.Andidepressant, the old and new.A review of the toxicity of generation of their adverse effects and toxicity in overdose.Emerg Med Clin North Am, 2000；18(4):637-54).Selective serotonin reuptake inhibitor mainly generates inhibiting effect to 5-HT transporter, It can effectively inhibit central nervous system presynaptic membrane to absorb 5-HT from synaptic cleft and in conjunction with 5-HT transporter, increase For the 5-HT actually utilized in gap, to achieve the purpose that treatment.
In all indications relevant to serotonin dysfunction, depression is most important, because defending according to the world Raw Organization, depression have become the fourth-largest burden property disease of the mankind.The year two thousand twenty is expected, the disability of depression adjusts the service life Annual meeting leaps to the second of all diseases.(Bromet E,Andrade LH,Hwang I,et al.,Cross-national epidemiology of DSM-IV major depressive episode.BMC Med.2011,9:90)。
However, the clinical research in relation to depression shows that the phenomenon that not responding to known SSRIs is very prominent, another It usually will appear delay through the therapeutic effect that commonly overlooked factor is SSRIs in anti depressant therapy, symptom is being treated sometimes It is former week in can also deteriorate.In addition, sex dysfunction is common side effect for SSRIs.It is therefore desirable to develop energy Enough compounds for improving treatment depression and other serotonin related diseases.
The present invention provides a kind of noval chemical compounds with serotonin reuptake transporter inhibitory activity, have preferable clinic and answer Use prospect.Compared with existing similar compound, the compound of the present invention has better drug effect, medicine for property and/or toxicity Learn characteristic.
Summary of the invention
Only summarize some aspects of the invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification When variant with citation, it is subject to the disclosure of the specification.
The present invention relates to a kind of novel (2- (heteroaryl oxygroup) phenyl) bridged piperazine derivatives, with 5-HT transporter (SERT) there is stronger binding affinity, 5-HT reuptake can be inhibited, so as to be used to prepare treatment central nervous system (CNS) drug of dysfunction, is especially used to prepare the drug of the treatment disturbance of emotion, and the disturbance of emotion includes but and unlimited In depression, anxiety disorder, social phobia, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, terrified barrier Hinder and posttraumatic stress disorder.
The compounds of this invention property is stablized, good security, has pharmacodynamics and pharmacokinetic advantage, such as good Brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., thus have compared with Good potential applicability in clinical practice.
Pharmaceutical composition the present invention also provides the method for preparing this kind of compound and containing such compound.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Q is-O- or-S-；
M is-O- ,-S- ,-CH2Or-NH-；
R and t is each independently 0 or 1；
N is 0,1,2,3,4 or 5；With
Each R1And R2With meaning of the present invention.
In one embodiment, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、- CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6The C that alkylamino or hydroxyl replace1-C6Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkyl halide Base, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、- CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1- C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4The C that alkylamino or hydroxyl replace1-C4Alkane Base.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogenated alkoxy.
In one embodiment, each R1It independently is H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、- CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2、 Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
In one embodiment, compound of the present invention for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination disclosed by the invention Object.
In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their any combination.
In one embodiment, pharmaceutical composition of the present invention, further comprising treatment central nervous system function The drug of the drug of energy obstacle, the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, as feelings Feel the salts drug of stabilizer, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, alternatively Drug, nervous stimulants, nicotinic antagonists or their any combination of property serotonin reuptake inhibitor.
In another embodiment, it is amitriptyline that the present invention, which treats the drug of central nervous system dysfunction, (amitriptyline), desipramine (desipramine), Mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), Prozac (fluoxetine), Trazodone (trazodone), Sertraline (sertraline), Duloxetine (duloxetine), Fluvoxamine (fluvoxamine), Milnacipran (milnacipran), left-handed Milnacipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), Venlafaxine (venlafaxine), Dapoxetine hydrochloride (dapoxetine), Nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), Citalopram (citalopram), escitalopram (escitalopram), Paxil (paroxetine), lithium carbonate (lithium Carbonate), buspirone (buspirone), Olanzapine (olanzapine), Quetiapine (quetiapine), Risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), Clozapine (clozapine), modafinil (modafinil), Mecamylamine (mecamylamine), card Ergot woods (cabergoline), adamantane (adamantane), imipramine (imipramine), Pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinindium (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), Pipamperone (pipamperone), dimension for smooth (vestipitant), Librium (chlordiazepoxide), perphenazine (perphenazine) or their any combination.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing, treating or mitigating central nervous system dysfunction.For example, in one embodiment, the drug is used for It prevents, treats or mitigates mammalian central nervous system dysfunction, in another embodiment, the drug is for pre- Anti-, treatment or the central nervous system dysfunction for mitigating people.
In one embodiment, the central nervous system dysfunction refers to depression, anxiety disorder, social phobia Disease, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, spirit point Split disease, sleep disturbance, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain barrier Hinder, cognitive disorder, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal Symptom and premenstrualtension syndrome.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing, treating or mitigating the disturbance of emotion.
In one embodiment, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, Obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for inhibiting serotonin reuptake transporter.
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
Biological results show that the compounds of this invention has strong affinity to source of people 5-HT transporter (SERT), because This compound provided by the invention can be used as preferable selective serotonin reuptake inhibitor.
In addition, there is some compounds of the present invention serotonin reuptake transporter inhibition and norepinephrine reuptake to inhibit Property synergy, other of the invention compounds have serotonin reuptake transporter inhibition and dopamine reuptake inhibition There are serotonin, norepinephrine and the triple reuptakes of dopamine to inhibit to make for synergy, the other compound of the present invention With.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry Description in March, John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, the article " one " used in the present invention, " one (kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment that one component is taken into account in the embodiment.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched It states and includes the case where the case where wherein event or situation occur and wherein it does not occur.For example, " optional key " refers to The key may exist or can be not present, and the description includes singly-bound, double or triple bonds.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or a kind of compound for being included as example, subclass and the present invention special inside embodiment.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, naphthenic base, heterocycle, Aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), etc..
Term " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF3、-CH2CF3、-CHFCH3、-CH2CH2F、 CF2CH3Deng.In one embodiment, C1-C6Halogenated alkyl includes fluorine-substituted C1-C6Alkyl；In another embodiment, C1- C4Halogenated alkyl includes fluorine-substituted C1-C4Alkyl；In yet another embodiment, C1-C4Halogenated alkyl includes fluorine-substituted C1-C2 Alkyl.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used to block or protect the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.14, A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document are included herein by reference.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonate, niacin Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through alkali appropriate Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any included N's The compound of group is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-C8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Term " therapeutically effective amount " refers to that when delivering medicine to main body to treat disease, the component of compound is enough to this disease The treatment of disease works." therapeutically effective amount " can be with the item of compound, disease and severity and main body to be treated Part, the age, weight, gender etc. and change.
Phenylpiperazine derivatives of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof can be with As selective serotonin reuptake inhibitor, to controlling for mankind's central nervous system dysfunction, the especially disturbance of emotion Treatment has potential purposes, and the disturbance of emotion includes but is not limited to that depression, social phobia, obsessive-compulsive disorder, is shied at anxiety disorder Probably breaking-out, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to and can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be and be used to prepare and/or purify compound shown in formula (I) and/or for separating compound shown in this formula (I) Enantiomer intermediate.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to the intermediates of compound shown in preparation formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or its individual stereoisomer, isomery The racemic or non-racemic mixture of body or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient agent are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；GennaroA.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be mentioned in the form of liposome, micella, microballoon or nanometer system For.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent or pulvis and excipient may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier used in effervescent or pulvis and excipient can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be in conjunction with the soluble polymer as target medicine carrier.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.
The purposes of the compounds of this invention and composition
Compound provided by the invention and pharmaceutical composition can be used for preparing for preventing, treating or mitigating mammal, The drug of central nervous system dysfunction including the mankind can be used for preparing the medicine for inhibiting serotonin reuptake transporter Product.
Specifically, the amount of compound effectively detectably can selectively inhibit 5- hydroxyl in composition of the invention The reuptake of tryptamines, the compound of the present invention can be used as treatment mankind's central nervous system (CNS) dysfunction, especially feelings Feel the drug of obstacle, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, obsessive-compulsive disorder, terrified Breaking-out, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate central nervous system dysfunction disease.It is described in response to serotonin The central nervous system dysfunction of regulation further comprises but is not limited to that depression, social phobia, is forced at anxiety disorder Disease, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, is slept at panic attack Dormancy obstacle, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognition Obstacle, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and Premenstrualtension syndrome etc..
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy is with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.
The use of logogram word below is through the present invention:
BOC, Boc tert-butoxycarbonyl
CH2Cl2, DCM methylene chloride
CDCl3Deuterated chloroform
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
EDTA ethylenediamine tetra-acetic acid
EtOAc, EA ethyl acetate
MeOH methanol
G grams
H hours
ML, ml milliliters
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention time
TFA trifluoroacetic acid
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
BSA bovine serum albumin
Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R1、R2 There is definition of the present invention with n.
Synthetic schemes 1
Synthetic method 1
Compound 3 can be prepared by following process: under [Pd] catalyst, alkali appropriate and heating condition, be changed Object 1 is closed to react to obtain intermediate 2 with the benzenethiol optionally replaced.Intermediate 2 slough Boc protection after, then with 3- oxetanone It is reacted at room temperature with sodium cyanoborohydride and obtains target compound 3.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
The synthesis of embodiment 1:1- (2- ((4- chlorphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
The synthesis of step 1) 4- (2- ((4- chlorphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
Successively by 4- (2- bromophenyl) piperazine -1- t-butyl formate (0.34g, 1.0mmol), to chlorothio-phenol (0.17g, 1.2mmol), bis- (2- diphenylphosphine) phenylates (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and anhydrous DMSO (10mL) is added in 50mL reaction flask, and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) is added under nitrogen protection. Reaction is warming up to 100 DEG C and reacts 24 hours.After reaction, it is cooled to room temperature, reaction solution adds water (40mL) to dilute, ethyl acetate Organic phase is collected in (20mLx 3) extraction, and anhydrous sodium sulfate is dry, and vacuum distillation removes solvent, and gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=20/1) and obtains title compound (white solid, 0.26g, 65.0%).
MS(ESI,pos.ion)m/z:405.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36~7.29 (m, 4H), 7.21~7.19 (m, 1H), 7.12 (d, J =7.9Hz, 1H), 6.95 (m, 1H), 6.88 (d, J=7.9Hz, 1H), 3.17 (s, 4H), 2.53 (s, 4H), 1.38 (s, 9H)
The synthesis of step 2) 1- (2- ((4- chlorphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
By 4- (2- ((4- chlorphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.24g, 0.6mmol) and dichloromethane Alkane (2mL) is added sequentially in 25mL reaction flask, and trifluoroacetic acid (1mL) then is added, and is reacted at room temperature 2 hours.After reaction, Vacuum distillation removes solvent and obtains grease.Gained grease is dissolved in anhydrous methanol (5mL), 3- oxa- is then sequentially added Cyclobutanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) after addition, react at room temperature 20 hours. Saturated aqueous ammonium chloride (40mL) washing is added, ethyl acetate (20mL x 3) extracts, collected organic layer, and anhydrous sodium sulfate is dry Dry, vacuum distillation removes solvent, and gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) Obtain title compound (white solid, 0.15g, 71.0%).
MS(ESI,pos.ion)m/z:361.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.34~7.26 (m, 4H), 7.19~7.16 (m, 1H), 7.10 (d, J =7.9Hz, 1H), 6.96 (m, 1H), 6.89 (d, J=7.8Hz, 1H), 4.67 (m, 4H), 3.55~3.51 (m, 1H), 3.10 (s,4H),2.46(s,4H)；
13C NMR(151MHz,CDCl3)δ(ppm):150.4,134.3,133.9,133.0,132.8,129.6,129.5, 127.3,124.6,120.4,75.6,59.4,51.4,50.0.
The synthesis of embodiment 2:1- (2- ((2,4 dichloro benzene base) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
The synthesis of step 1) 4- (2- ((2,4 dichloro benzene base) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.34g, 1.0mmol), 2,4 dichloro benzene thiophenol (0.22g, 1.2mmol), bis- (2- diphenylphosphine) benzene Ether (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolates and purifies (petrol ether/ethyl acetate (v/v)=20/1) and obtains title compound (white solid, 0.04g, 10.0%).
MS(ESI,pos.ion)m/z:439.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.46 (d, J=2.1Hz, 1H), 7.27~7.25 (m, 1H), 7.10~ 7.08 (m, 2H), 7.07 (d, J=8.3Hz, 1H), 7.01~6.96 (m, 2H), 3.11 (s, 4H), 2.38 (s, 4H), 1.35 (s, 9H).
The synthesis of step 2) 1- (2- ((2,4 dichloro benzene base) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((2,4- bis- Chlorphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.26g, 0.6mmol) and trifluoroacetic acid (1mL) be in methylene chloride Room temperature reaction in (2mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) prepared within room temperature reaction 20 hours in methanol (5mL) with sodium cyanoborohydride (0.08g, 1.2mmol).Gained slightly produces Object carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.18g, 75.0%).
MS(ESI,pos.ion)m/z:395.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45 (d, J=2.1Hz, 1H), 7.27~7.24 (m, 1H), 7.12~ 7.09 (m, 2H), 7.07 (d, J=8.4Hz, 1H), 7.01~6.96 (m, 2H), 4.67 (t, J=6.6Hz, 2H), 4.63 (t, J =6.2Hz, 2H), 3.54~3.51 (m, 1H), 3.10 (s, 4H), 2.39 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):151.6,136.3,133.4,133.2,131.5,129.7,128.6, 127.6,124.6,120.8,75.6,59.3,51.3,50.0.
The synthesis of embodiment 3:1- (oxetanylmethoxy -3- base) -4- (2- (p-methylphenyl sulfenyl) phenyl) piperazine
The synthesis of step 1) 4- (2- (p-methylphenyl sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.40g, 1.18mmol), to methylbenzene phenyl-sulfhydrate (0.175g, 1.41mmol), bis- (2- diphenylphosphines) Phenylate (0.54g, 0.1mmol), sodium tert-butoxide (0.283g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (light yellow liquid, 0.30g, 66.2%).
MS(ESI,pos.ion)m/z:385.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (d, J=8.1Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 7.10~7.09 (m, 1H), 7.05 (dd, J=7.9,1.5Hz, 1H), 6.92~6.86 (m, 1H), 6.74 (dd, J=7.9, 1.1Hz,1H),3.11(s,4H),2.50(s,4H),2.37(s,3H),1.38(s,9H).
The synthesis of step 2) 1- (oxetanes -3- base) -4- (2- (p-methylphenyl sulfenyl) phenyl) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. (2- is (to methylbenzene by 4- Base sulfenyl) phenyl) piperazine -1- t-butyl formate (0.20g, 0.52mmol) and trifluoroacetic acid (4mL) be in methylene chloride (8mL) Room temperature reaction is evaporated under reduced pressure after reaction and removes solvent, gained grease and 3- oxetanone (0.06g, 0.78mmol) It is prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.065g, 1.04mmol).Gained crude product carries out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.15g, 84.7%).
MS(ESI,pos.ion)m/z:341.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37 (d, J=8.0Hz, 2H), 7.19 (d, J=8.0Hz, 2H), 7.12~7.09 (m, 1H), 7.07 (dd, J=7.9,1.5Hz, 1H), 6.92~6.88 (m, 1H), 6.74 (dd, J=7.9, 1.1Hz, 1H), 4.68 (dt, J=14.8,6.4Hz, 4H), 3.58~3.54 (m, 1H), 3.12 (s, 4H), 2.52 (s, 4H), 2.37(s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.2,138.4,135.0,134.5,130.3,129.3,127.6, 126.0,124.5,119.9,75.6,59.3,51.2,50.0,21.3.
The synthesis of embodiment 4:1- (2- ((4- methoxyphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
The synthesis of step 1) 4- (2- ((4- methoxyphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.50g, 1.47mmol), to methoxybenzenethiol (0.303g, 2.20mmol), bis- (2- diphenyl Phosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 140 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (light yellow liquid, 0.45g, 76.6%).
MS(ESI,pos.ion)m/z:401.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43~7.41 (m, 2H), 7.05 (dd, J=5.1,1.4Hz, 2H), 6.94~6.92 (m, 2H), 6.90~6.88 (m, 1H), 6.61 (d, J=7.8Hz, 1H), 3.81 (s, 3H), 3.14 (s, 4H), 2.54(s,4H),1.38(s,9H).
The synthesis of step 2) 1- (2- ((4- methoxyphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((4- methoxy Base phenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.45g, 1.12mmol) and trifluoroacetic acid (4mL) be in methylene chloride Room temperature reaction in (8mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.121g, 1.68mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.14g, 2.24mmol).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.32g, 80.2%).
MS(ESI,pos.ion)m/z:357.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.46~7.41 (m, 2H), 7.07 (dd, J=5.1,1.4Hz, 2H), 6.95~6.91 (m, 2H), 6.91~6.85 (m, 1H), 6.63 (d, J=7.7Hz, 1H), 4.72~4.64 (m, 4H), 3.83 (s, 3H), 3.61~3.57 (m, 1H), 3.12 (s, 4H), 2.54 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.2,148.6,136.9,136.2,126.4,125.6,124.5, 122.7,119.9,115.2,75.6,59.3,55.4,51.2,50.0.
The synthesis of embodiment 5:1- (oxetanylmethoxy -3- base) -4- (2- (aminomethyl phenyl sulfenyl) phenyl) piperazine
The synthesis of step 1) 4- (2- (aminomethyl phenyl sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.80g, 2.35mmol), 3- methylbenzene phenyl-sulfhydrate (0.379g, 3.06mmol), bis- (2- diphenylphosphines) Phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.562g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (light yellow liquid, 0.42g, 46.4%).
MS(ESI,pos.ion)m/z:385.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.26 (s, 1H), 7.23 (dd, J=4.5,2.5Hz, 2H), 7.15~ 7.11 (m, 2H), 7.06 (dd, J=7.9,1.2Hz, 1H), 6.93~6.91 (m, 1H), 6.82 (dd, J=7.9,1.4Hz, 1H),3.12(s,4H),2.50(s,4H),2.33(s,3H),1.38(s,9H).
The synthesis of step 2) 1- (oxetanes -3- base) -4- (2- (aminomethyl phenyl sulfenyl) phenyl) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- (methylbenzene Base sulfenyl) phenyl) piperazine -1- t-butyl formate (0.40g, 1.04mmol) and trifluoroacetic acid (4mL) be in methylene chloride (8mL) Room temperature reaction, after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.112g, 1.56mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.13g, 1.20mmol).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.21g, 59.3%).
MS(ESI,pos.ion)m/z:341.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.28 (s, 1H), 7.24 (dd, J=4.6,2.6Hz, 2H), 7.16~ 7.11 (m, 2H), 7.08 (dd, J=7.9,1.2Hz, 1H), 6.94~6.90 (m, 1H), 6.84 (dd, J=7.9,1.4Hz, 1H), 4.70~4.65 (m, 4H), 3.59~3.55 (m, 1H), 3.12 (s, 4H), 2.49 (s, 4H), 2.33 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.7,139.2,134.3,134.1,133.2,130.7,129.2, 128.8,128.6,126.5,124.4,120.0,75.5,59.3,51.2,49.9,21.3.
The synthesis of embodiment 6:1- (2- ((3- methoxyphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
The synthesis of step 1) 4- (2- ((3- methoxyphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.50g, 1.47mmol), 3- methoxybenzenethiol (0.308g, 2.20mmol), bis- (2- diphenyl Phosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (light yellow liquid, 0.41g, 64.6%).
MS(ESI,pos.ion)m/z:401.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.25~7.23 (m, 1H), 7.16~7.13 (m, 1H), 7.06 (dd, J =7.9,1.3Hz, 1H), 7.02~6.99 (m, 1H), 6.96 (dd, J=2.4,1.7Hz, 1H), 6.95~6.91 (m, 2H), 6.86~6.85 (m, 1H), 3.75 (s, 3H), 3.12 (s, 4H), 2.48 (s, 4H), 1.37 (s, 9H)
The synthesis of step 2) 1- (2- ((3- methoxyphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((3- methoxy Base phenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.41g, 1.02mmol) and trifluoroacetic acid (4mL) be in methylene chloride Room temperature reaction in (8mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.11g, 1.53mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.128g, 2.04mmol).Gained Crude product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.30g, 82.6%).
MS(ESI,pos.ion)m/z:357.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.27~7.23 (m, 1H), 7.16~7.14 (m, 1H), 7.08 (dd, J =8.0,1.2Hz, 1H), 7.02~7.00 (m, 1H), 6.97 (dd, J=2.4,1.7Hz, 1H), 6.95~6.90 (m, 2H), 6.86~6.84 (m, 1H), 4.69~4.64 (m, 4H), 3.76 (s, 3H), 3.58~3.53 (m, 1H), 3.11 (s, 4H), 2.48 (s,4H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.2,148.6,136.9,136.2,126.4,125.6,124.5, 122.7,119.9,115.2,75.6,59.3,55.4,51.2,50.0.
The synthesis of embodiment 7:1- (2- ((4- fluorophenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
The synthesis of step 1) 4- (2- ((4- fluorophenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.50g, 1.47mmol), to fluoro thiophenol (0.283g, 2.20mmol), bis- (2- diphenylphosphine) benzene Ether (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (light yellow liquid, 0.43g, 75.3%).
MS(ESI,pos.ion)m/z:389.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.44~7.40 (m, 2H), 7.15~7.12 (m, 1H), 7.08 (d, J =1.4Hz, 1H), 7.08~7.05 (m, 2H), 6.94~6.90 (m, 1H), 6.72 (dd, J=7.9,1.3Hz, 1H), 3.11 (s,4H),2.51(s,4H),1.38(s,9H).
The synthesis of step 2) 1- (2- ((4- fluorophenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((4- fluorobenzene Base) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.33g, 0.85mmol) and trifluoroacetic acid (4mL) be at methylene chloride (8mL) Middle room temperature reaction, after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.092g, 1.28mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.107g, 1.70mmol).Gained Crude product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.157g, 53.8%).
MS(ESI,pos.ion)m/z:345.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45~7.40 (m, 2H), 7.15~7.11 (m, 1H), 7.09 (d, J =1.4Hz, 1H), 7.08~7.05 (m, 2H), 6.94~6.89 (m, 1H), 6.74 (dd, J=7.9,1.3Hz, 1H), 4.70~ 4.66 (m, 4H), 3.60~3.55 (m, 1H), 3.11 (s, 4H), 2.50 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):163.7,162.0,149.4,136.1,134.4,127.9,126.5, 124.6,120.2,116.7,116.5,75.5,59.3,51.2,49.9.
The conjunction of embodiment 8:1- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine At
The synthesis of step 1) 4- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (0.34g, 1.00mmol), 2,4- thiophenol dimethyl benzene (0.17g, 1.20mmol), bis- (2- diphenyl Phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolate and purify (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (light yellow liquid, 0.28g, 70.0%).
MS(ESI,pos.ion)m/z:399.50[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (d, J=7.8Hz, 1H), 7.16 (s, 1H), 7.08~7.04 (m, 2H), 7.03 (d, J=7.6Hz, 1H), 6.89~6.85 (m, 1H), 6.54 (d, J=7.6Hz, 1H), 3.16~3.13 (m, 4H), 2.55~2.53 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H), 1.36 (s, 9H)
The synthesis of step 2) 1- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((2,4- bis- Aminomethyl phenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.24g, 0.60mmol) and trifluoroacetic acid (4mL) be in methylene chloride Room temperature reaction in (8mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.08g, 1.20mmol).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.16g, 75.2%).
MS(ESI,pos.ion)m/z:355.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37 (d, J=7.8Hz, 1H), 7.15 (s, 1H), 7.08~7.02 (m, 2H), 7.01 (d, J=7.6Hz, 1H), 6.88~6.85 (m, 1H), 6.51 (d, J=7.6Hz, 1H), 4.71~4.68 (m, 4H), 3.63~3.59 (m, 1H), 3.14~3.11 (m, 4H), 2.56~2.51 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.1,142.5,139.4,136.3,134.7,131.8,128.0, 126.3,125.6,124.6,120.0,75.7,59.4,51.3,50.2,21.3,20.7.
Embodiment 9:1- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- aminomethyl phenyl) -4- (oxetanylmethoxy -3- base) piperazine The synthesis of piperazine
The synthesis of step 1) 4- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- aminomethyl phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- methyl of 2- Phenyl) it is piperazine -1- t-butyl formate (0.60g, 1.69mmol), 2,4- thiophenol dimethyl benzene (0.303g, 2.20mmol), double (2- diphenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.406g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (light yellow solid, 0.45g, 64.6%).
MS(ESI,pos.ion)m/z:413.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.34 (d, J=7.8Hz, 1H), 7.15 (s, 1H), 7.02 (d, J= 7.7Hz, 1H), 6.94 (d, J=8.0Hz, 1H), 6.89 (dd, J=8.0,1.3Hz, 1H), 6.38 (d, J=1.4Hz, 1H), 3.60(s,4H),2.98(s,4H),2.37(s,3H),2.33(s,3H),2.13(s,3H),1.50(s,9H).
Step 2) 1- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- aminomethyl phenyl) -4- (oxetanylmethoxy -3- base) piperazine Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((2,4- fluorine Phenyl) sulfenyl) -4- aminomethyl phenyl) piperazine -1- t-butyl formate (0.40g, 0.97mmol) and trifluoroacetic acid (4mL) be in dichloro Room temperature reaction in methane (8mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.14g, 1.45mmol) and sodium cyanoborohydride (0.122g, 1.94mmol) are made for room temperature reaction 20 hours in methanol (6mL) It is standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) and obtains title compound (white Solid, 0.152g, 42.6%).
MS(ESI,pos.ion)m/z:369.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.35 (d, J=7.8Hz, 1H), 7.14 (s, 1H), 7.02 (d, J= 7.7Hz, 1H), 6.99 (d, J=8.0Hz, 1H), 6.89 (dd, J=8.0,1.4Hz, 1H), 6.34 (d, J=1.4Hz, 1H), 4.74~4.63 (m, 4H), 3.61~3.57 (m, 1H), 3.10 (s, 4H), 2.53 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H),2.12(s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):146.8,142.1,139.0,135.8,134.2,131.6,128.2, 127.8,126.9,126.3,119.8,75.6,59.3,51.4,50.1,21.2,21.0,20.6.
The synthesis of embodiment 10:4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- (phenylsulfartyl) cyanophenyl
The synthesis of step 1) 4- (4- cyano -2- (phenylsulfartyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), benzenethiol (0.13g, 1.20mmol), bis- (2- diphenylphosphines) Phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolates and purifies (petrol ether/ethyl acetate (v/v)=15/1) and obtains title compound (white solid, 0.29g, 72.6%).
MS(ESI,pos.ion)m/z:396.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.44~7.42 (m, 5H), 7.37 (dd, J=8.4,1.8Hz, 1H), 7.07 (d, J=8.3Hz, 1H), 6.98 (d, J=1.7Hz, 1H), 3.19 (s, 4H), 2.50 (s, 4H), 1.38 (s, 9H)
The synthesis of step 2) 4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- (phenylsulfartyl) cyanophenyl
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- (phenylsulfartyl) phenyl) piperazine -1- t-butyl formate (0.24g, 0.6mmol) and trifluoroacetic acid (1mL) be at methylene chloride (2mL) Middle room temperature reaction, after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) prepared within room temperature reaction 20 hours in methanol (5mL) with sodium cyanoborohydride (0.08g, 1.2mmol).Gained slightly produces Object carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.18g, 84.1%).
MS(ESI,pos.ion)m/z:352.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.44~7.40 (m, 5H), 7.38 (dd, J=8.3,1.8Hz, 1H), 7.05 (d, J=8.3Hz, 1H), 6.99 (d, J=1.7Hz, 1H), 4.68 (t, J=6.6Hz, 2H), 4.64 (t, J=6.2Hz, 2H), 3.57~3.55 (m, 1H), 3.18 (s, 4H), 2.50 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):153.2,135.5,134.3,131.5,131.2,130.4,130.0, 129.3,120.0,119.0,107.2,75.5,59.3,50.7,49.6.
Embodiment 11:3- ((4- methoxyphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl Synthesis
The synthesis of step 1) 4- (4- cyano -2- ((4- methoxyphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), to methoxybenzenethiol (0.17g, 1.20mmol), bis- (2- bis- Phenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=15/1) and obtains title compound (white solid, 0.22g, 52.0%).
MS(ESI,pos.ion)m/z:426.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43~7.41 (m, 2H), 7.33~7.31 (m, 1H), 7.02~ 6.99 (m, 1H), 6.97~6.96 (m, 2H), 6.80 (s, 1H), 3.87 (s, 3H), 3.18 (s, 4H), 2.57 (s, 4H), 1.38 (s,9H).
The conjunction of step 2) 3- ((4- methoxyphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl At
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4- methoxyphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.26g, 0.60mmol) and trifluoroacetic acid (4mL) be two Room temperature reaction in chloromethanes (8mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) are made for room temperature reaction 20 hours in methanol (6mL) It is standby.It is (white that gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound Color solid, 0.32g, 80.2%).
MS(ESI,pos.ion)m/z:382.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42~7.41 (m, 2H), 7.34~7.32 (m, 1H), 7.03~ 7.01 (m, 1H), 6.97~6.95 (m, 2H), 6.81 (s, 1H), 4.70 (t, J=6.4Hz, 2H), 4.66 (t, J=6.1Hz, 2H), 3.87 (s, 3H), 3.60~3.57 (m, 1H), 3.17 (s, 4H), 2.55 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):161.1,152.3,137.9,137.5,129.6,120.5,119.8, 119.3,116.0,107.4,75.6,59.4,55.6,50.9,49.8.
Embodiment 12:3- ((3- methoxyphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl Synthesis
The synthesis of step 1) 4- (4- cyano -2- ((3- methoxyphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), 3- methoxybenzenethiol (0.17g, 1.20mmol), bis- (2- bis- Phenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=15/1) and obtains title compound (white solid, 0.20g, 48.0%).
MS(ESI,pos.ion)m/z:426.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38~7.36 (m, 1H), 7.32~7.29 (m, 1H), 7.04~ 7.01 (m, 3H), 6.97~6.94 (m, 2H), 3.82 (s, 3H), 3.17 (s, 4H), 2.51 (s, 4H), 1.38 (s, 9H)
The conjunction of step 2) 3- ((3- methoxyphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl At
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((3- methoxyphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.26g, 0.60mmol) and trifluoroacetic acid (4mL) be two Room temperature reaction in chloromethanes (8mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) are made for room temperature reaction 20 hours in methanol (6mL) It is standby.It is (white that gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound Color solid, 0.13g, 57.0%).
MS(ESI,pos.ion)m/z:382.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37~7.35 (m, 1H), 7.32~7.30 (m, 1H), 7.04~ 7.01 (m, 3H), 6.97~6.95 (m, 2H), 4.69 (t, J=6.5Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.80 (s, 3H), 3.58~3.55 (m, 1H), 3.18 (s, 4H), 2.51 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.7,153.3,135.5,132.3,131.7,130.9,130.5, 126.50,120.0,119.6,119.1,115.1,107.3,75.6,59.3,55.6,50.9,49.7.
Embodiment 13:4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- ((4- (trifluoromethyl) phenyl) sulfenyl) The synthesis of cyanophenyl
The conjunction of step 1) 4- (4- cyano -2- ((4- (trifluoromethyl) phenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate At
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), to trifluoromethyl thiophenol (0.21g, 1.20mmol), bis- (2- Diphenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=15/1) obtain title compound (white solid, 0.09g, 20.0%).
MS(ESI,pos.ion)m/z:464.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.60~7.56 (m, 2H), 7.51~7.49 (m, 1H), 7.39~ 7.36 (m, 2H), 7.31~7.28 (m, 1H), 7.10 (d, J=8.3Hz, 1H), 3.18 (s, 4H), 2.41 (s, 4H), 1.38 (s, 9H).
Step 2) 4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- ((4- (trifluoromethyl) phenyl) sulfenyl) cyanophenyl Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4- trifluoromethyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.28g, 0.60mmol) and trifluoroacetic acid (4mL) exist Room temperature reaction in methylene chloride (8mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) are made for room temperature reaction 20 hours in methanol (6mL) It is standby.It is (white that gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound Color solid, 0.18g, 73.0%).
MS(ESI,pos.ion)m/z:420.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.60~7.56 (m, 2H), 7.51~7.48 (m, 1H), 7.39~ 7.36 (m, 2H), 7.31~7.28 (m, 1H), 7.10 (d, J=8.3Hz, 1H), 4.67 (t, J=6.5Hz, 2H), 4.61 (t, J =6.1Hz, 2H), 3.55~3.50 (m, 1H), 3.19 (s, 4H), 2.40 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.1,138.3,135.2,132.3,131.6,131.3,126.6, 126.5,120.6,118.7,107.2,75.5,59.3,50.8,49.6.
The conjunction of embodiment 14:4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- (p-methylphenyl sulfenyl) cyanophenyl At
The synthesis of step 1) 4- (4- cyano -2- (p-methylphenyl sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), to methylbenzene phenyl-sulfhydrate (0.15g, 1.20mmol), bis- (2- hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolate and purify (petrol ether/ethyl acetate (v/v)=15/1) obtain title compound (light yellow liquid, 0.19g, 46.2%).
MS(ESI,pos.ion)m/z:410.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37~7.35 (m, 3H), 7.22 (d, J=7.9Hz, 2H), 7.05 (d, J=8.2Hz, 1H), 6.89 (d, J=1.4Hz, 1H), 3.16 (s, 4H), 2.54 (s, 4H), 2.41 (s, 3H), 1.38 (s, 9H).
The synthesis of step 2) 4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- (p-methylphenyl sulfenyl) cyanophenyl
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- (p-methylphenyl sulfenyl) phenyl) piperazine -1- t-butyl formate (0.25g, 0.60mmol) and trifluoroacetic acid (4mL) be in methylene chloride Room temperature reaction in (8mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.08g, 1.20mmol).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtain title compound (white solid, 0.16g, 75.8%).
MS(ESI,pos.ion)m/z:366.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37~7.35 (m, 3H), 7.24 (d, J=7.9Hz, 2H), 7.04 (d, J=8.2Hz, 1H), 6.89 (d, J=1.4Hz, 1H), 4.69 (t, J=6.5Hz, 2H), 4.66 (t, J=6.2Hz, 2H), 3.59~3.56 (m, 1H), 3.17 (s, 4H), 2.54 (s, 4H), 2.41 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.7,140.0,137.0,135.3,131.1,130.4,129.9, 127.0,119.9,119.2,107.3,75.6,59.4,50.9,49.8,21.5.
The conjunction of embodiment 15:4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- (aminomethyl phenyl sulfenyl) cyanophenyl At
The synthesis of step 1) 4- (4- cyano -2- (aminomethyl phenyl sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), 3- methylbenzene phenyl-sulfhydrate (0.15g, 1.20mmol), bis- (2- hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolate and purify (petrol ether/ethyl acetate (v/v)=15/1) obtain title compound (light yellow liquid, 0.36g, 89.0%).
MS(ESI,pos.ion)m/z:410.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (dd, J=8.2,1.8Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.28 (s, 1H), 7.23 (t, J=8.1Hz, 2H), 7.02 (d, J=8.3Hz, 1H), 6.99 (d, J=1.7Hz, 1H), 3.16(s,4H),2.51(s,4H),2.36(s,3H),1.38(s,9H).
The synthesis of step 2) 4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) -3- (aminomethyl phenyl sulfenyl) cyanophenyl
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- (aminomethyl phenyl sulfenyl) phenyl) piperazine -1- t-butyl formate (0.25g, 0.60mmol) and trifluoroacetic acid (4mL) be in dichloromethane Room temperature reaction in alkane (8mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) prepared within room temperature reaction 20 hours in methanol (6mL) with sodium cyanoborohydride (0.08g, 1.20mmol).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtain title compound (white solid, 0.16g, 75.7%).
MS(ESI,pos.ion)m/z:366.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37 (dd, J=8.2,1.8Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 7.28 (s, 1H), 7.24 (t, J=8.1Hz, 2H), 7.04 (d, J=8.3Hz, 1H), 6.97 (d, J=1.7Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.58 (m, 1H), 3.18 (s, 4H), 2.52 (s, 4H), 2.37 (s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.9,140.0,136.1,135.2,131.7,131.1,130.6, 130.3,130.1,129.9,119.9,119.1,107.2,75.5,59.3,50.8,49.7,21.4.
Embodiment 16:3- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) benzene The synthesis of nitrile
The synthesis of step 1) 4- (4- cyano -2- ((2,4- 3,5-dimethylphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), 2,4- thiophenol dimethyl benzene (0.17g, 1.20mmol), bis- (2- Diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 130 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product into Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.33g, 78.2%).
MS(ESI,pos.ion)m/z:424.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.35~7.32 (m, 2H), 7.19 (s, 1H), 7.07~7.03 (m, 2H), 6.66~6.63 (m, 1H), 3.21 (s, 4H), 2.58 (s, 4H), 2.38 (d, J=4.6Hz, 3H), 2.28 (d, J= 4.7Hz,3H),1.38(s,9H).
Step 2) 3- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((2,4- 3,5-dimethylphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.25g, 0.60mmol) and trifluoroacetic acid (4mL) exist Room temperature reaction in methylene chloride (8mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) are made for room temperature reaction 20 hours in methanol (6mL) It is standby.It is (white that gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound Color solid, 0.18g, 79.0%).
MS(ESI,pos.ion)m/z:380.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.33~7.31 (m, 2H), 7.19 (s, 1H), 7.07~7.05 (m, 2H), 6.66~6.62 (m, 1H), 4.66~4.72 (m, 4H), 3.62~3.59 (m, 1H), 3.20 (s, 4H), 2.57 (s, 4H), 2.39 (d, J=4.6Hz, 3H), 2.28 (d, J=4.7Hz, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.7,142.8,140.8,136.8,136.4,132.5,129.6, 129.1,128.6,125.8,119.9,119.3,107.4,75.6,59.4,50.8,49.8,21.4,20.7.
The conjunction of embodiment 17:3- ((4- fluorophenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl At
The synthesis of step 1) 4- (4- cyano -2- ((4- fluorophenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.00mmol), 4- fluoro thiophenol (0.15g, 1.2mmol), bis- (2- diphenyl Phosphine) phenylate (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolates and purifies (petrol ether/ethyl acetate (v/v)=15/1) and obtains title compound (white solid, 0.08g, 20.0%).
MS(ESI,pos.ion)m/z:414.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45~7.41 (m, 2H), 7.39 (dd, J=8.2,1.8Hz, 1H), 7.13 (t, J=8.6Hz, 2H), 7.06 (d, J=8.2Hz, 1H), 6.88 (d, J=1.8Hz, 1H), 3.17 (s, 4H), 2.52 (s,4H),1.36(s,9H).
The synthesis of step 2) 3- ((4- fluorophenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4- fluorophenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.25g, 0.6mmol) and trifluoroacetic acid (1mL) be in dichloromethane Room temperature reaction in alkane (2mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) prepared within room temperature reaction 20 hours in methanol (5mL) with sodium cyanoborohydride (0.08g, 1.2mmol).Gained slightly produces Object carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.13g, 56.7%).
MS(ESI,pos.ion)m/z:370.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45~7.40 (m, 2H), 7.39 (dd, J=8.2,1.8Hz, 1H), 7.14 (t, J=8.5Hz, 2H), 7.06 (d, J=8.2Hz, 1H), 6.89 (d, J=1.8Hz, 1H), 4.70 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.59~3.55 (m, 1H), 3.17 (s, 4H), 2.53 (s, 4H)；
13C NMR(151MHz,CDCl3) δ (ppm): 164.4,162.8,152.8,137.0 (d, J=7.6Hz), 136.1, 130.6,130.3,126.1 (d, J=4.5Hz), 120.1,118.9,117.5,117.4,107.4,75.5,59.3,50.8, 49.7.
The conjunction of embodiment 18:3- ((4- chlorphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl At
The synthesis of step 1) 4- (4- cyano -2- ((4- chlorphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.50g, 1.37mmol), 4- chlorothio-phenol (0.296g, 2.05mmol), bis- (2- hexichol Base phosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.384g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography It isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (white solid, 0.15g, 27.2%).
MS(ESI,pos.ion)m/z:430.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42 (dd, J=13.0,5.0Hz, 2H), 7.40~7.34 (m, 2H), 7.29~7.24 (m, 1H), 7.08~6.98 (m, 2H), 3.59 (s, 4H), 3.06 (s, 4H), 1.49 (s, 9H)
The synthesis of step 2) 3- ((4- chlorphenyl) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4- chlorphenyl) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.14g, 0.33mmol) and trifluoroacetic acid (1mL) be in dichloromethane Room temperature reaction in alkane (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.036g, 0.5mmol) and sodium cyanoborohydride (0.042g, 0.66mmol) are made for room temperature reaction 20 hours in methanol (5mL) It is standby.It is (white that gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtains title compound Color solid, 0.105g, 82.7%).
MS(ESI,pos.ion)m/z:386.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.41 (dd, J=8.3,1.9Hz, 1H), 7.40~7.37 (m, 2H), 7.37~7.32 (m, 2H), 7.06 (d, J=8.3Hz, 1H), 7.02 (d, J=1.8Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.64 (t, J=6.2Hz, 2H), 3.67~3.54 (m, 1H), 3.16 (s, 4H), 2.49 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):153.3,135.4,135.2,134.6,131.8,130.7,130.1, 129.9,120.1,118.7,107.3,75.4,59.2,50.7,49.5.
Embodiment 19:3- ((2,4 dichloro benzene base) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl Synthesis
The synthesis of step 1) 4- (4- cyano -2- ((2,4 dichloro benzene base) sulfenyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- cyano of 2- Phenyl) piperazine -1- t-butyl formate (0.37g, 1.0mmol), 2,4 dichloro benzene thiophenol (0.22g, 1.2mmol), bis- (2- hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolates and purifies (petrol ether/ethyl acetate (v/v)=15/1) and obtains title compound (white solid, 0.23g, 49.0%).
MS(ESI,pos.ion)m/z:464.11[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.53 (s, 1H), 7.45 (dd, J=8.3,1.8Hz, 1H), 7.26~ 7.23 (m, 2H), 7.09 (d, J=8.3Hz, 1H), 7.01 (d, J=1.8Hz, 1H), 3.19 (s, 4H), 2.46 (s, 4H), 1.37 (s,9H).
The conjunction of step 2) 3- ((2,4 dichloro benzene base) sulfenyl) -4- (4- (oxetanylmethoxy -3- base) piperazine -1- base) cyanophenyl At
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (4- cyano -2- ((2,4 dichloro benzene base) sulfenyl) phenyl) piperazine -1- t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) are prepared for room temperature reaction 20 hours in methanol (5mL). Gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtains title compound, and (white is solid Body, 0.13g, 49.7%).
MS(ESI,pos.ion)m/z:420.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.54 (s, 1H), 7.47 (dd, J=8.3,1.8Hz, 1H), 7.24~ 7.21 (m, 2H), 7.09 (d, J=8.3Hz, 1H), 7.00 (d, J=1.7Hz, 1H), 4.68 (t, J=6.6Hz, 2H), 4.63 (t, J=6.2Hz, 2H), 3.55 (m, 1H), 3.19 (s, 4H), 2.46 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):154.2,138.3,135.7,135.5,132.6,132.1,131.6, 130.6,129.9,128.3,120.5,118.7,107.5,75.5,59.3,50.7,49.7.
Embodiment 20:1- (oxetanylmethoxy -3- base) -4- (2- (phenylsulfartyl) -4- (trifluoromethyl) phenyl) piperazine Synthesis
The synthesis of step 1) 4- (2- (phenylsulfartyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) piperazine -1- t-butyl formate (0.41g, 1.0mmol), benzenethiol (0.13g, 1.2mmol), bis- (2- hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out column layer Analysis isolates and purifies (petrol ether/ethyl acetate (v/v)=30/1) and obtains title compound (white solid, 0.24g, 54.3%).
MS(ESI,pos.ion)m/z:439.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42~7.40 (m, 2H), 7.39~7.35 (m, 4H), 7.10 (d, J =8.3Hz, 1H), 7.08 (d, J=1.5Hz, 1H), 3.16 (s, 4H), 2.49 (s, 4H), 1.38 (s, 9H)
The synthesis of step 2) 1- (oxetanylmethoxy -3- base) -4- (2- (phenylsulfartyl) -4- (trifluoromethyl) phenyl) piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e.,4- (2- (phenyl sulphur Base) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate(0.26g, 0.6mmol) and trifluoroacetic acid (1mL) are in dichloromethane Room temperature reaction in alkane (2mL), after reaction, vacuum distillation remove solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) prepared within room temperature reaction 20 hours in methanol (5mL) with sodium cyanoborohydride (0.08g, 1.2mmol).Gained slightly produces Object carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (white solid, 0.16g, 65.6%).
MS(ESI,pos.ion)m/z:395.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42~7.40 (m, 2H), 7.39~7.36 (m, 4H), 7.11 (d, J =8.3Hz, 1H), 7.07 (d, J=1.5Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.56 ~3.53 (m, 1H), 3.16 (s, 4H), 2.48 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.7,134.5,133.6,132.3,129.7,128.7,126.3, 125.9 (d, J=39.6Hz), 125.0,123.7,123.2,119.9,75.6,59.3,51.0,49.8.
Embodiment 21:1- (oxetanylmethoxy -3- base) -4- (2- (p-methylphenyl sulfenyl) -4- (trifluoromethyl) phenyl) The synthesis of piperazine
The synthesis of step 1) 4- (2- (p-methylphenyl sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) it is piperazine -1- t-butyl formate (0.41g, 1.0mmol), 4- methylbenzene phenyl-sulfhydrate (0.15g, 1.2mmol), double (2- diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product into Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.32g, 71.2%).
MS(ESI,pos.ion)m/z:453.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (s, 1H), 7.35~7.31 (m, 2H), 7.22 (d, J= 8.0Hz, 2H), 7.11 (d, J=8.3Hz, 1H), 6.97 (d, J=1.6Hz, 1H), 3.18 (s, 4H), 2.54 (s, 4H), 2.40 (s,3H),1.38(s,9H).
Step 2) 1- (oxetanylmethoxy -3- base) -4- (2- (p-methylphenyl sulfenyl) -4- (trifluoromethyl) phenyl) piperazine Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. (2- is (to methylbenzene by 4- Base sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (0.27g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) are prepared for room temperature reaction 20 hours in methanol (5mL). Gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound, and (white is solid Body, 0.21g, 86.6%).
MS(ESI,pos.ion)m/z:409.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (s, 1H), 7.35~7.32 (m, 2H), 7.22 (d, J= 7.9Hz, 2H), 7.10 (d, J=8.3Hz, 1H), 6.97 (d, J=1.6Hz, 1H), 4.70 (t, J=6.6Hz, 2H), 4.67 (t, J=6.2Hz, 2H), 3.59~3.56 (m, 1H), 3.16 (s, 4H), 2.53 (s, 4H), 2.40 (s, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.0,139.3,136.0,134.6,130.7,127.9,126.4, 126.2,125.1,124.5,123.1,119.7,75.6,59.4,51.0,49.9,21.4.
Embodiment 22:1- (oxetanylmethoxy -3- base) -4- (2- (aminomethyl phenyl sulfenyl) -4- (trifluoromethyl) phenyl) The synthesis of piperazine
The synthesis of step 1) 4- (2- (aminomethyl phenyl sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) it is piperazine -1- t-butyl formate (0.41g, 1.0mmol), 3- methylbenzene phenyl-sulfhydrate (0.15g, 1.2mmol), double (2- diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product into Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.27g, 60.0%).
MS(ESI,pos.ion)m/z:453.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (dd, J=8.4,1.6Hz, 1H), 7.28~7.25 (m, 2H), 7.22 (d, J=7.8Hz, 1H), 7.17 (d, J=7.8Hz, 1H), 7.12 (d, J=8.3Hz, 1H), 7.08 (d, J=1.7Hz, 1H),3.17(s,4H),2.51(s,4H),2.35(s,3H),1.38(s,9H).
Step 2) 1- (oxetanylmethoxy -3- base) -4- (2- (aminomethyl phenyl sulfenyl) -4- (trifluoromethyl) phenyl) piperazine Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- (methylbenzene Base sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (0.27g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) are prepared for room temperature reaction 20 hours in methanol (5mL). Gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound, and (white is solid Body, 0.21g, 86.6%).
MS(ESI,pos.ion)m/z:409.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (dd, J=8.3,1.6Hz, 1H), 7.27~7.25 (m, 2H), 7.23 (d, J=7.8Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 7.07 (d, J=1.7Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.66 (t, J=6.2Hz, 2H), 3.57~3.54 (m, 1H), 3.16 (s, 4H), 2.50 (s,4H),2.35(s,3H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.6,139.7,135.0,134.3,131.9,130.8,129.6, 126.5,126.3,126.1,125.9,125.6,125.0,123.5,123.2,119.8,75.6,59.4,51.0,49.8, 21.4.
Embodiment 23:1- (2- ((3- methoxyphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- Base) piperazine synthesis
The conjunction of step 1) 4- (2- (3- methoxyphenyl sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate At
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) it is piperazine -1- t-butyl formate (0.41g, 1.0mmol), 3- methoxybenzenethiol (0.17g, 1.2mmol), double (2- diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product into Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.14g, 30.0%).
MS(ESI,pos.ion)m/z:469.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.40 (dd, J=8.3,1.7Hz, 1H), 7.30 (t, J=8.1Hz, 1H), 7.16 (d, J=1.6Hz, 1H), 7.12 (d, J=8.3Hz, 1H), 7.00 (d, J=7.7Hz, 1H), 6.96~6.97 (m, 1H), 6.90~6.88 (m, 1H), 3.78 (s, 3H), 3.16 (s, 4H), 2.49 (s, 4H), 1.37 (s, 9H)
Step 2) 1- (2- ((3- methoxyphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- base) The synthesis of piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- (methylbenzene Base sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) are prepared for room temperature reaction 20 hours in methanol (5mL). Gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound, and (white is solid Body, 0.21g, 47.9%).
MS(ESI,pos.ion)m/z:425.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (dd, J=8.3,1.5Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.15 (d, J=1.6Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 7.01 (d, J=7.7Hz, 1H), 6.96~6.94 (m, 1H), 6.90~6.87 (m, 1H), 4.69 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.78 (s, 3H), 3.57 (m,1H),3.16(s,4H),2.49(s,4H)；
13C NMR(151MHz,CDCl3)δ(ppm):160.5,152.8,134.2,133.6,131.0,130.5,128.9, 126.1,125.6,123.9,119.9,118.4,114.6,75.6,59.4,55.5,51.0,49.8.
Embodiment 24:1- (2- ((4- methoxyphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- Base) piperazine synthesis
The conjunction of step 1) 4- (2- (4- methoxyphenyl sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate At
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) it is piperazine -1- t-butyl formate (0.41g, 1.0mmol), 4- methoxybenzenethiol (0.17g, 1.2mmol), double (2- diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and tris(dibenzylideneacetone) dipalladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product into Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.19g, 40.0%).
MS(ESI,pos.ion)m/z:469.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43~7.41 (m, 2H), 7.31 (dd, J=8.3,1.5Hz, 1H), 7.11 (d, J=8.2Hz, 1H), 6.97~6.96 (m, 1H), 6.95~6.93 (m, 1H), 6.86 (d, J=1.7Hz, 1H), 3.83(s,3H),3.16(s,4H),2.54(s,4H),1.38(s,9H).
Step 2) 1- (2- ((4- methoxyphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- base) The synthesis of piperazine
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. (2- is (to methylbenzene by 4- Base sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL).After reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) are prepared for room temperature reaction 20 hours in methanol (5mL). Gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound, and (white is solid Body, 0.11g, 44.0%).
MS(ESI,pos.ion)m/z:425.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43~7.40 (m, 2H), 7.31 (dd, J=8.3,1.5Hz, 1H), 7.10 (d, J=8.2Hz, 1H), 6.97~6.95 (m, 2H), 6.86 (d, J=1.7Hz, 1H), 4.70 (t, J=6.6Hz, 2H), 4.67 (t, J=6.2Hz, 2H), 3.85 (s, 3H), 3.60~3.56 (m, 1H), 3.16 (s, 4H), 2.55 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):160.7,151.5,137.1,126.7,126.4,126.2,125.1, 123.3,122.7,121.4,119.6,115.6,75.6,59.4,55.5,51.0,49.9.
Embodiment 25:1- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy - 3- yl) piperazine synthesis
Step 1) 4- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate Synthesis
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) piperazine -1- t-butyl formate (0.41g, 1.0mmol), 2,4- thiophenol dimethyl benzene (0.17g, 1.2mmol), Bis- (2- diphenylphosphine) phenylates (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetones) two Palladium (23mg, 0.025mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product Carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.44g, 95.0%).
MS(ESI,pos.ion)m/z:467.25[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.35 (d, J=7.8Hz, 1H), 7.30 (dd, J=8.2,1.6Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.2Hz, 1H), 7.07 (d, J=7.8Hz, 1H), 6.70 (d, J=2.0Hz, 1H), 3.16(s,4H),2.55(s,4H),2.37(s,3H),2.29(s,3H),1.38(s,9H).
Step 2) 1- (2- ((2,4- 3,5-dimethylphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- Base) piperazine synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((2,4- bis- Aminomethyl phenyl) sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) room temperature reaction in methylene chloride (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxa- Cyclobutanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) room temperature reaction 20 hours in methanol (5mL) Preparation.It is (white that gained crude product progress column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound Color solid, 0.13g, 51.5%).
MS(ESI,pos.ion)m/z:423.18[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.36 (d, J=7.8Hz, 1H), 7.31 (dd, J=8.3,1.6Hz, 1H), 7.17 (s, 1H), 7.11 (d, J=8.2Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 6.72 (d, J=1.8Hz, 1H), 4.71 (t, J=6.6Hz, 2H), 4.68 (t, J=6.2Hz, 2H), 3.61~3.58 (m, 1H), 3.18 (s, 4H), 2.56 (s, 4H),2.37(s,3H),2.29(s,3H)；
13C NMR(151MHz,CDCl3)δ(ppm):151.9,142.4,140.1,136.3,135.6,132.1,128.3, 126.6,126.2,125.1,123.0,122.7,119.7,75.6,59.4,51.0,49.9,21.4,20.6.
Embodiment 26:1- (2- ((4- chlorphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- base) The synthesis of piperazine
The synthesis of step 1) 4- (2- ((4- chlorphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e. 4- (the bromo- 4- (three of 2- Methyl fluoride) phenyl) it is piperazine -1- t-butyl formate (0.60g, 1.47mmol), 4- chlorothio-phenol (0.318g, 2.2mmol), double (2- diphenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and tris(dibenzylideneacetone) dipalladium (46mg, 0.05mmol) 100 DEG C of reaction reaction in 24 hours preparations under nitrogen protection in DMSO (10mL).Gained crude product carries out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.29g, 41.7%).
MS(ESI,pos.ion)m/z:474.05[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.40 (dd, J=8.3,1.6Hz, 1H), 7.36~7.31 (m, 4H), 7.13 (d, J=1.7Hz, 1H), 7.08 (d, J=8.3Hz, 1H), 3.53 (s, 4H), 3.02 (s, 4H), 1.48 (s, 9H)
Step 2) 1- (2- ((4- chlorphenyl) sulfenyl) -4- (trifluoromethyl) phenyl) -4- (oxetanylmethoxy -3- base) piperazine Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 4- (2- ((4- chlorobenzene Base) sulfenyl) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (0.29g, 0.61mmol) and trifluoroacetic acid (1mL) exist Room temperature reaction in methylene chloride (2mL), after reaction, vacuum distillation removes solvent, gained grease and 3- oxetanone (0.066g, 0.92mmol) and sodium cyanoborohydride (0.077g, 1.22mmol) are made for room temperature reaction 20 hours in methanol (5mL) It is standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) and obtains title compound (white Solid, 0.229g, 87.7%).
MS(ESI,pos.ion)m/z:429.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.40 (dd, J=8.3,1.6Hz, 1H), 7.36~7.30 (m, 4H), 7.14~7.10 (m, 2H), 4.68 (t, J=6.6Hz, 2H), 4.64 (t, J=6.2Hz, 2H), 3.57~3.53 (m, 1H), 3.14(s,4H),2.46(s,4H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.9,134.5,134.2,133.44,131.2,129.8, 126.3,126.2,124.1,123.9,120.0,75.4,59.2,50.9,49.6.
Biologic test
Embodiment A: the affinity of humanization 5-HT transporter of the evaluation compound to expression in Chinese hamster ovary celI
Experimental method
Under the conditions of 22 DEG C, to cell membrane homogenate albumen (12 μ g), 2nM [3H] imipramine and buffer (50mM Tris-HCl (pH 7.4), 120mMNaCl, 5mM KCl and 0.1%BSA) formed mixed system in, be added or be added without survey Compound is tried, is incubated for 60 minutes altogether.
And in the mixed system of above-mentioned condition, 10 μM of imipramine are added, for measuring non-specific binding value.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum conditions by pre- dipped The glass fiber filter (GF/B, Packard) of 0.3%PEI quickly filters, and using ice-cold 50mM Tris-HCl and 150mMNaCl repeated flushing is several times.Dry filter membrane uses scintillation solution in scintillation counter (Topcount, Packard) (Microscint 0, Packard) calculates remaining radioactivity.Experimental result is with special relative to control group radioligand Property combine suppression percentage indicate.
Standard reference compound is imipramine, competition linearity curve is obtained by the experiment test of series of concentrations, to calculate IC out50.As a result referring to Table A, Table A is affinity experimental result of the compounds of this invention to humanization 5-HT transporter (SERT).
Affinity measurement result of the Table A the compounds of this invention to source of people 5-HT transporter (SERT)
Experimental result shows that the compounds of this invention has stronger affinity to source of people 5-HT transporter (SERT).
Embodiment B: rat intravenous or stomach-filling quantify the Pharmacokinetic Evaluation after the compounds of this invention
The present invention assesses the compounds of this invention in the intracorporal pharmacokinetic of rat, and animal information is detailed in Table B.
Table B animal subject information table of the present invention
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline The form of aqueous solution or 10%DMSO+10%KolliphorHS 15+80% normal saline solution, to animal subject carry out to Medicine.For be injected intravenously administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and at 3,000 or 4,000rpm from The heart 10 minutes, plasma solutions are collected, and save at -20 DEG C or -70 DEG C.For gastric infusion group, dosage 2.5mg/ Kg or 5mg/kg, vein takes when then time point upon administration is 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour Blood (0.3mL), and be centrifuged 10 minutes at 3,000 or 4,000rpm, plasma solutions are collected, and protect at -20 DEG C or -70 DEG C It deposits.
The plasma solutions obtained are collected to above-mentioned each group carries out LC/MS/MS analysis.Analysis the result shows that, in rat body The compounds of this invention measured by way of intravenous injection administration and gastric infusion has exposure magnitude big, and clearance rate is low, raw The preferable pharmacokinetic properties such as object availability height.Illustrate that the compounds of this invention druggability is more preferable, there is better clinic to answer Use prospect.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (10)

1. a kind of compound is the pharmaceutically acceptable salt of compound shown in formula (I) compound represented or formula (I),
Wherein:
Q is-O- or-S-；
M is-O- ,-S- ,-CH2Or-NH-；
R and t is each independently 0 or 1；
N is 0,1,2,3,4 or 5；
Each R1It independently is H, D, F, Cl, Br, I, C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Haloalkoxy Base or C1-C6Alkylthio group；With
R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1- C6Halogenated alkoxy.
2. compound according to claim 1, wherein each R1It independently is H, D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogen Substituted alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy or C1-C4Alkylthio group.
3. compound according to claim 1, wherein R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、C1-C4Alkane Base, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogenated alkoxy.
4. compound according to claim 1 or 2, wherein each R1It independently is H, D, F, Cl, Br, I, methyl, ethyl, just Propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
5. compound according to claim 1 or 3, wherein R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH, first Base, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
6. compound according to claim 1 for the compound with one of following structure or has one of following knot The pharmaceutically acceptable salt of the compound of structure:
7. a kind of pharmaceutical composition includes compound as claimed in any one of claims 1 to 6；With
Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any Combination.
8. pharmaceutical composition according to claim 7 further includes treatment central nervous system dysfunction Drug, the drug of the treatment central nervous system dysfunction is amitriptyline, desipramine, Mirtazapine, Bupropion, auspicious Bo Xiting, Prozac, Trazodone, Sertraline, Duloxetine, Fluvoxamine, Milnacipran, left-handed Milnacipran, first text is gone to draw Method is pungent, vilazodone, Venlafaxine, Dapoxetine hydrochloride, Nefazodone, femoxetine, chlorimipramine, Citalopram, Escitalopram Pulan, Paxil, lithium carbonate, buspirone, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Aripiprazole, piperazine sieve Grand, Clozapine, modafinil, Mecamylamine, Cabergoline, adamantane, imipramine, Pramipexole, thyroxine, right U.S. are husky Sweet smell, quinindium, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, Pipamperone, dimension are for smooth, sharp It sleeps peaceful, perphenazine or their any combination.
9. pharmaceutical composition described in compound as claimed in any one of claims 1 to 6 or claim 7-8 any one exists The purposes in drug is prepared, the drug is for preventing, treating or mitigating central nervous system dysfunction.
10. purposes according to claim 9, the drug is for preventing, treating or mitigating the disturbance of emotion.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1606548A (en) * 2001-12-20 2005-04-13 H·隆德贝克有限公司 Aryloxyphenyl and arylsulfanylphenyl piperazine derivatives
CN101056878A (en) * 2004-11-12 2007-10-17 施瓦茨制药有限公司 Azaindole carboxamides
WO2013026455A1 (en) * 2011-08-24 2013-02-28 Aarhus Universitet Permanently positively charged antidepressants

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8791112B2 (en) * 2011-03-30 2014-07-29 Arrien Pharmaceuticals Llc Substituted 5-(pyrazin-2-yl)-1H-pyrazolo [3, 4-B] pyridine and pyrazolo [3, 4-B] pyridine derivatives as protein kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1606548A (en) * 2001-12-20 2005-04-13 H·隆德贝克有限公司 Aryloxyphenyl and arylsulfanylphenyl piperazine derivatives
CN101056878A (en) * 2004-11-12 2007-10-17 施瓦茨制药有限公司 Azaindole carboxamides
WO2013026455A1 (en) * 2011-08-24 2013-02-28 Aarhus Universitet Permanently positively charged antidepressants

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder;Benny Bang-Andersen 等;《J. Med. Chem.》;20110412;第54卷;3206-3221

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