CN105859703A - Preparation method of novel brexpiprazole, aripiprazole and salts thereof - Google Patents
Preparation method of novel brexpiprazole, aripiprazole and salts thereof Download PDFInfo
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- CN105859703A CN105859703A CN201510033843.6A CN201510033843A CN105859703A CN 105859703 A CN105859703 A CN 105859703A CN 201510033843 A CN201510033843 A CN 201510033843A CN 105859703 A CN105859703 A CN 105859703A
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- 0 *CCCCCc1ccc(CCC(N2)=C)c2c1 Chemical compound *CCCCCc1ccc(CCC(N2)=C)c2c1 0.000 description 20
- QBHOMFFQYUMDKG-DPMKTTEJSA-N C/C=C1\C=CC(C=CC(C)=C2)C2=C=NC1 Chemical compound C/C=C1\C=CC(C=CC(C)=C2)C2=C=NC1 QBHOMFFQYUMDKG-DPMKTTEJSA-N 0.000 description 1
- QQSRVGNGYDHJGX-UHFFFAOYSA-N C=CCCCCOc1ccc(C=CC(C2)=O)c2c1 Chemical compound C=CCCCCOc1ccc(C=CC(C2)=O)c2c1 QQSRVGNGYDHJGX-UHFFFAOYSA-N 0.000 description 1
- XEFLSAFQVMCXDO-UHFFFAOYSA-N C=NSC1=CC=CCC1 Chemical compound C=NSC1=CC=CCC1 XEFLSAFQVMCXDO-UHFFFAOYSA-N 0.000 description 1
- BNIQQCYVFAGCPS-UHFFFAOYSA-N CCCCCC[IH]c1ccc(C=CC(N2)=O)c2c1 Chemical compound CCCCCC[IH]c1ccc(C=CC(N2)=O)c2c1 BNIQQCYVFAGCPS-UHFFFAOYSA-N 0.000 description 1
- KWYVUIOJWIENHG-UHFFFAOYSA-N CCCCCCc1cc(NC(CC2)=O)c2cc1 Chemical compound CCCCCCc1cc(NC(CC2)=O)c2cc1 KWYVUIOJWIENHG-UHFFFAOYSA-N 0.000 description 1
- XIJMIUPLFZOEAQ-UHFFFAOYSA-N CCCCCOc(cc1)cc(C2)c1C=CC2=O Chemical compound CCCCCOc(cc1)cc(C2)c1C=CC2=O XIJMIUPLFZOEAQ-UHFFFAOYSA-N 0.000 description 1
- SKQNDBJWFDQZIK-UHFFFAOYSA-N N#CCCCCOc1cc(OC(CC2)=O)c2cc1 Chemical compound N#CCCCCOc1cc(OC(CC2)=O)c2cc1 SKQNDBJWFDQZIK-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of novel Brexpiprazole and salts thereof, aripiprazole and salts thereof, or key intermediates thereof. The method uses a starting material of 7-hydroxycoumarin or 7-hydroxy dehydrocoumarin, which is subjected to a substitution reaction, a dehydrogenation reaction and / or amination reaction. The method has the advantages of sufficient supply of easily available raw materials, low cost, high safety, simple operation, high product yield and good quality, and is suitable for enlarge production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to cloth auspicious piperazine azoles, Aripiprazole or the salt both it, the preparation method of intermediate.
Background technology
Cloth auspicious piperazine azoles (Brexpiprazole, code name: OPC-34712) Shi great Pharmaceutical Co., Ltd research and development antipsychotic drug of new generation, it acts on multiple receptor, is d2 dopamine receptor partial agonist, 5-HT2A receptor antagonist, α 1 adrenoceptor antagonists.At present, the III clinical trial phase as auxiliary treatment major depressive disorder (MDD) medicine is carried out at US and European；In the U.S., Europe and Japan carry out treating schizoid III clinical trial phase, meanwhile, also carry out the II clinical trial phase of adult mild brain disturbance in the U.S..
Big Pharmaceutical Co., Ltd discloses the syntheti c route of cloth auspicious piperazine azoles in PCT application WO2006112464A1, sees reaction equation 1.
Reaction equation 1:
Wherein, raw material 7-(4-neoprene epoxide)-1H-quinoline-2-one is prepared by 7-hydroxyl-1H-quinoline-2-one and 1-bromo-4-chlorobutane, sees reaction equation 2:
Reaction equation 2:
For 7-hydroxyl-1H-quinoline-2-one, document Synthesis, 1997, (1), report its preparation method in 87 90, see reaction equation 3.
Reaction equation 3:
The method is with m-anisidine as raw material, and first with cinnamoyl chloride generation amidation process, then in the presence of aluminum chloride, cyclization generates 7-hydroxyl-1H-quinoline-2-one.Owing to selectivity is poor, when preparing 7-hydroxyl-1H-quinoline-2-one, by the generation with the substantial amounts of by-product 5-hydroxyl-1H-quinoline-2-one being not readily separated.This impurity will participate in series reaction below, thus have impact on purity and the yield of finished product cloth auspicious piperazine azoles.Therefore, it is necessary to find the variation route of economic, practical, an applicable industrialized production, to improve technology stability and product quality.
Summary of the invention
For above-mentioned weak point, it is an object of the present invention to provide that one new, easy and simple to handle, yield is high, low cost prepare cloth auspicious piperazine azoles and salt, Aripiprazole and salt thereof or the synthetic route of their key intermediate.
The invention provides cloth auspicious piperazine azoles and salt, Aripiprazole and salt thereof, cloth auspicious piperazine azoles and the preparation method of aripiprazole intermediate, described method is one of following method:
Method one: being prepared compound I or its salt by compound II or its salt through aminating reaction, reaction equation is as follows:
Wherein, Z is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl
It is expressed as singly-bound or double bond；
Or
Method two: being prepared compound 1 or its salt by compound 2 or its salt through dehydrogenation reaction, reaction equation is as follows:
Wherein, U is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl
Y is O or NH,
Condition is, when U is Br or 2, during 3-Dichlorobenzene base-1-piperazinyl, and when being reaction under oxidant existence condition, Y is not NH.
In the process, described dehydrogenation reaction includes that compound 1 or its salt are prepared in the reaction under oxidant existence condition of compound 2 or its salt, also including that compound 2 or its salt obtain intermediate 3 or its salt by halogenating reaction, then reacted by elimination and prepare compound 1 or its salt, reaction equation is as follows:
Wherein, X is halogen (preferably Cl, Br, iodine).
Below method one and two is further elaborated respectively.
(1) method one:
1. in described method one, whenRepresent double bond, and Z is 1-(benzothiophene-4-base) piperazinyl or 2, during 3-Dichlorobenzene base-1-piperazinyl, described compound II is embodied as compound IIa, the product Compound I of described aminating reaction is embodied as compound shown in Formulas I a, described method one i.e.:
Products therefrom compound Ia is cloth auspicious piperazine azoles or OPC-14857 (Aripiprazole metabolite).
2. in described method one, whenRepresenting singly-bound, and Z is 1 (benzothiophene 4 base) piperazinyl or 2, during 3 Dichlorobenzene base 1 piperazinyl, described compound II is embodied as compound IIb, and described method one may further include:
Compound IIb or its salt carrying out dehydrogenation reaction and obtains compound IIa or its salt, then carry out aminating reaction and obtain compound Ia, reaction equation is as follows:
Or
Described method one may further include: compound IIb or its salt carrying out aminating reaction and obtains compound Ib or its salt, then compound Ib carries out dehydrogenation reaction and obtains compound Ia or its salt, and reaction equation is as follows
Products therefrom compound Ib is Aripiprazole.
Products therefrom compound Ia is cloth auspicious piperazine azoles or OPC-14857 (Aripiprazole metabolite).
3. in described method one; when Z is halogen (preferably Cl, Br), leaving group (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen); described compound II is embodied as compound IIc, IId.Described method one may further include:
Compound IIc, IId or its salt being carried out substitution reaction obtain compound IIa, IIb or its salt with compound IV or its salt, then carry out aminating reaction and obtain compound Ia, Ib or its salt, reaction equation is as follows
Or
Compound IIc, IId or its salt carrying out aminating reaction and obtains compound Ic, Id or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ia, Ib or its salt, reaction equation is as follows
Wherein, R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
It is expressed as singly-bound or double bond, whenWhen representing double bond, compound II is expressed as IIc, compound I and is expressed as Ic, whenWhen representing singly-bound, compound II is expressed as IId, compound I and is expressed as Id, Ia, Ib.
4. in described method one, whenRepresent double bond; and Z is when being halogen (preferably Cl, Br), leaving group (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), described compound II is embodied as compound IIc.Described method one may further include:
Compound IIc or its salt being carried out substitution reaction obtain compound IIa or its salt with compound IV or its salt, then carry out aminating reaction and obtain compound Ia or its salt, reaction equation is as follows
Or
Compound IIc or its salt carrying out aminating reaction and obtains compound Ic or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ia or its salt, reaction equation is as follows
Wherein, R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
5. in described method one, whenRepresent singly-bound; and Z is when being halogen (preferably Cl, Br), leaving group (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen); described compound II is embodied as compound IId, and described method one may further include:
Compound IId or its salt are carried out dehydrogenation reaction and obtains compound IIc or its salt, then compound IIc or its salt are carried out substitution reaction obtain compound IIa or its salt with compound IV or its salt, carrying out aminating reaction again and obtain compound Ia or its salt, reaction equation is as follows
Or
Compound IId or its salt being carried out substitution reaction obtain compound IIb or its salt with compound IV or its salt, then carry out dehydrogenation reaction and obtain compound IIa or its salt, then carry out aminating reaction and obtain compound Ia or its salt, reaction equation is as follows
Or
Compound IId or its salt carrying out aminating reaction and obtains compound Id or its salt, then carry out dehydrogenation reaction and obtain compound Ic or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ia or its salt, reaction equation is as follows
Or
Compound IId or its salt carrying out aminating reaction and obtains compound Id or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ib or its salt, then carry out dehydrogenation reaction and obtain compound Ia or its salt, reaction equation is as follows
Wherein, R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring.
In described method one, compound IIc and IId can be substituted reaction in the presence of a base and prepare by the compound shown in general formula III with compound VI or its salt:
Wherein, X1For halogen atom or leaving group (i.e. with the same group that can cause substitution reaction of halogen atom)；Be preferably Cl, Br, OH, OMs, OTf or p-toluenesulfonyl OTs, Zc andAs defined above, Zc and X1Can be the same or different.
(2) method two:
1. in described method two, when Y represents NH, and Z is 1-(benzothiophene-4-base) piperazinyl or 2, during 3-Dichlorobenzene base-1-piperazinyl, described compound 2 is embodied as compound 2a, the product Compound 1 of described dehydrogenation reaction is embodied as compound shown in formula 1a, described method two i.e.:
Products therefrom compound 1a is cloth auspicious piperazine azoles or OPC-14857 (Aripiprazole metabolite).
2., in described method two, when Y represents O, and Z is 1 (benzothiophene 4 base) piperazinyl or 2, and during 3 Dichlorobenzene base 1 piperazinyl, described compound 2 is embodied as compound 2b, and described method two may further include:
Compound 2b or its salt carrying out aminating reaction and obtains compound 2a or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows:
Or
Compound 2b or its salt carrying out dehydrogenation reaction and obtains compound 1b or its salt, then carry out aminating reaction and obtain compound 1a or its salt, reaction equation is as follows
Wherein, the definition of Ua is same as described above.
Products therefrom compound 2a is Aripiprazole.
Products therefrom compound 1a is cloth auspicious piperazine azoles or OPC-14857 (Aripiprazole metabolite).
3. in described method two; when U be halogen (preferably Cl, Br) or leaving group (when being i.e. similar to group (preferably OH, OMs, OTf, the p-toluenesulfonyl OTs) that can cause substitution reaction of halogen, described method two may further include:
Before carrying out dehydrogenation reaction, with compound IV, compound 2c, 2d or its salt being carried out substitution reaction and obtain compound 2a, 2b or its salt, then carry out dehydrogenation reaction and obtain compound 1a, 1b or its salt, reaction equation is as follows
Or
Compound 2c, 2d or its salt carrying out dehydrogenation reaction and obtains compound 1c, 1d or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1a, 1b or its salt, reaction equation is as follows
Wherein, R1 and R2 is Cl, or R1 and R2 constitutes benzothienyl together with coupled phenyl ring；
Y is O or NH, and when Y is NH, compound 2 is expressed as 2c, and compound 1 is expressed as 1c, and when Y is O, compound 2 is expressed as 2d, and compound 1 is expressed as 1d；
Condition is, when Uc is Br or 2, during 3-Dichlorobenzene base-1-piperazinyl, and when being reaction under oxidant existence condition, Y is not NH.
4. in described method two; when U is halogen (preferably Cl, Br) or leaving group (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen) and time Y represents NH; described compound 2 is embodied as compound 2c, and described method two may further include:
Compound 2c or its salt and compound IV or its salt carrying out substitution reaction and obtains compound 2a or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows
Or
Compound 2c or its salt being carried out dehydrogenation reaction and obtains compound 1c or its salt, carry out substitution reaction with compound IV or its salt and obtain compound 1a or its salt, reaction equation is as follows
5. in described method two; when U is halogen (preferably Cl, Br) or leaving group (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen) and time Y represents O; described compound 2 is embodied as compound 2d, and described method two may further include:
Compound 2d or its salt carrying out aminating reaction and obtains compound 1d or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1b or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows
Or
Compound 2d or its salt being carried out substitution reaction obtain compound 2b or its salt with compound IV or its salt, then carry out aminating reaction and obtain compound 2a or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows
Or
Compound 2d or its salt carrying out dehydrogenation reaction and obtains compound 1d or its salt, then carry out aminating reaction and obtain compound 1c or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1a or its salt, reaction equation is as follows
Or
Compound 2d or its salt carrying out dehydrogenation reaction and obtains compound 1d or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1b or its salt, then carry out aminating reaction and obtain compound 1a or its salt, reaction equation is as follows
Wherein, R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring.
In described method two, compound 2c and 2d can be bought or be substituted with compound VI or its salt in the presence of a base by compound 4 reaction and prepare by market:
Wherein, X1For halogen atom or leaving group (i.e. with the same group that can cause substitution reaction of halogen atom)；Being preferably Cl, Br, OH, OMs, OTf or p-toluenesulfonyl (OTs), Uc's and Y is as defined above, Uc and X1Can be the same or different.
In described method one and two, when there is multistep reaction it is, described each step reaction can be carried out respectively, next step reaction is carried out again after will often walking product separating-purifying, or can also be carried out continuously according to one kettle way, the reaction of the most each step is carried out continuously, each step product purification without isolation, directly carries out next step reaction.
A preferred technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or its salt or OPC-14857 or the method for its salt, and its reaction equation is as follows,
Described method includes:
(1) make compound IIc and compound IV or its salt carry out substitution reaction and generate compound IIa；
(2) state directly up and reaction system adds amination reagent carry out aminating reaction and obtain compound Ia or its salt；
Wherein, Zc is halogen atom or leaving group (being i.e. similar to the group that can cause substitution reaction of halogen)；It is preferably Cl, Br, OMs, OTf or p-toluenesulfonyl (OTs).
R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
Za is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl.
An also optimal technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below,
The method comprises the following steps:
(1) compound 2c Yu 1-(benzothiophene-4-base) piperazine (compound IV-1) or its salt generation substitution reaction is made to generate compound 2a-1；
(2) state directly up and reaction system adds dehydrating agent carry out dehydrogenation reaction and obtain cloth auspicious piperazine azoles (compound 1a-1) or its salt；
Wherein, Uc is halogen (preferably Cl and Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), and Ua is 1-(benzothiophene-4-base) piperazinyl.
An also optimal technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below,
The method comprises the following steps:
(1) make compound 2c carry out dehydrogenation reaction and obtain compound 1c；
(2) state addition 1-(benzothiophene-4-base) piperazine (compound IV-1) or its salt generation substitution reaction in reaction system directly up and obtain cloth auspicious piperazine azoles (compound 1a-1) or its salt；
Wherein, Uc is that (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen, Ua is 1-(benzothiophene-4-base) piperazinyl for halogen (preferably Cl and Br) or other leaving groups..
An also optimal technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) compound IId Yu 1-(benzothiophene-4-base) piperazine (compound IV-1) or its salt generation substitution reaction is made to generate compound IIb-1；
(2) state addition dehydrating agent in reaction system directly up and carry out dehydrogenation reaction generation compound IIa-1；
(3) state directly up and reaction system adds amination reagent carry out aminating reaction and obtain cloth auspicious piperazine azoles (compound Ia-1) or its salt；
Wherein, Zc is that (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen, Za is 1-(benzothiophene-4-base) piperazinyl for halogen (preferably Cl and Br) or other leaving groups..
An also optimal technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) compound 2d Yu 1-(benzothiophene-4-base) piperazine (compound IV-1) or its salt generation substitution reaction is made to generate compound 2b-1；
(2) state addition amination reagent in reaction system directly up and carry out aminating reaction generation compound 2a-1；
(3) state directly up and reaction system adds dehydrating agent carry out dehydrogenation reaction and obtain cloth auspicious piperazine azoles (compound 1a-1) or its salt；
Wherein, Uc is that (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen, Ua is 1-(benzothiophene-4-base) piperazinyl for halogen (preferably Cl and Br) or other leaving groups.
Another technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or its salt or Aripiprazole or the method for its salt, and its reaction equation is as follows,
Described method includes:
(1) compound 2c and compound IV or its salt generation substitution reaction is made to generate compound 2a；
(2) state directly up and reaction system adds halide reagent carry out halogenating reaction and obtain compound 3a or its salt；
(3) compound 3a or its salt carry out eliminating reaction in the presence of with or without alkali and obtain cloth auspicious piperazine azoles or its salt or OPC-14857 (i.e. the metabolite of Aripiprazole) or its salt；
Wherein, Uc is halogen (preferably Cl and Br) or other leaving groups (are i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen; Ua is 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl, X is bromine, chlorine, iodine.
Another technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or its salt or Aripiprazole or the method for its salt, and its reaction equation is as follows,
Described method includes:
(1) in compound 2c, addition halide reagent carries out halogenating reaction and obtains compound 3c or its salt
(2) compound 3c or its salt carry out eliminating reaction in the presence of with or without alkali and obtain compound 1c；
(3) state directly up and reaction system adds compound IV or its salt generation substitution reaction generation compound 1a；
Wherein, Uc is halogen (preferably Cl and Br) or other leaving groups; (i.e. it is similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen; Ua is 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl, X is bromine, chlorine, iodine.
An also technical scheme of the present invention provides a kind of one kettle way and prepares cloth auspicious piperazine azoles or its salt or OPC-14857 or the method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) compound 2d and compound IV or its salt generation substitution reaction is made to generate compound 2b；
(2) state addition halide reagent in reaction system directly up and carry out halogenating reaction generation compound 3a；
(3) compound 3a directly carries out eliminating reacting generating compound 1b in the presence of with or without alkali；
(4) state directly up and reaction system adds amination reagent carry out aminating reaction and obtain cloth auspicious piperazine azoles or its salt or Aripiprazole or its salt；
Wherein, Uc is halogen (preferably Cl and Br) or other leaving groups (are i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen; Ua is 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl, X is bromine, chlorine, iodine.
In the above-mentioned methods, described aminating reaction is carried out in the presence of amination reagent.One or more in ammonia, carbamide, ammonium acetate, ammonium chloride, ammonium formate, ammonia of described amination reagent；Preferably, described amination reagent is ammonia, ammonia or ammonium acetate.
Described aminating reaction can be carried out in water or nonaqueous solvent, it is also possible to solubilizer is not carried out；Preferably, described solvent is selected from water, C1～C5 lower alcohol, N, one or more in dinethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide, acetonitrile, described C1～C5 lower alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propylene glycol or glycerol；It is highly preferred that described solvent is one or more in water, methanol, ethanol, DMF, dimethyl sulfoxide, hexamethyl phosphoramide, acetonitrile.The reaction temperature of described aminating reaction does not limits, and can be 0 DEG C～250 DEG C, preferably room temperature～150 DEG C.
In the above-mentioned methods, described dehydrogenation reaction includes that compound 1 is prepared in compound 2 reaction under oxidant existence condition, also includes that compound 2 prepares compound 1 by halo, elimination reaction through intermediate 3, and reaction equation is as follows:
In above-mentioned method of dehydrogenating, described reaction under oxidant existence condition.Described oxidant is selected from O2、Br2、H2O2、MnO2, 2,3-bis-chloro-5,6-dicyan 1,4-benzoquinone (DDQ), H2NOH-HCl、NBS、NaI、AlCl3, PhSeCl, BuLi (butyl lithium), Me3SiN=CMeOSiMe3, EtN=C=N (CH2)3NMe2Deng, it is also possible to add azodiisobutyronitrile (AIBN), Pd (OAc)2、t-Bu3P、AcOH、AcONa、K2CO3、(PhCO2)2、EtN(Pr-i)2Deng.The reaction dissolvent of described dehydrogenation reaction can be water or nonaqueous solvent, and described nonaqueous solvent is selected from dioxane, Carbon bisulfide, acetic acid, DMF, alkyl halide (dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.), ethers (THF, ether), DMF, DMSO, aromatic hydrocarbon solvent (chlorobenzene, dimethylbenzene, toluene etc.).The temperature of described dehydrogenation reaction does not limits, preferably-20～150 DEG C.
In above-mentioned method of dehydrogenating, described dehydrogenation reaction can also include carrying out dehydrogenation by halo, elimination reaction.Described halogenating reaction is carried out in the presence of halogenating agent in a solvent, and described halogenating agent is selected from Br2、I2、Cl2、PCl5、SO2Cl2, described solvent be one or more in oxolane, carbon tetrachloride, ethyl acetate, acetic acid, chloroform, ethanol, dioxane, N,N-dimethylformamide, benzene.The temperature of described halogenating reaction does not limits, preferably-20～150 DEG C.
Described elimination reaction is carried out in the presence of with or without alkali in a solvent；Described alkali is inorganic base or organic base；Preferably, described inorganic base is sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, described organic base is 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, quinoline, metal hydride, DMAP or organic amine, wherein, described organic amine is triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine；It is highly preferred that described inorganic base is sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, sodium sulfide or sodium hydrogen, described organic base is triethylamine, diethylamine, diisopropylamine or diisopropylethylamine；Described solvent is selected from water, ether solvent, halogenated hydrocarbon, aromatic hydrocarbon solvent (such as benzene,toluene,xylene), C1～C5 lower alcohol；One or more in esters, ketone, acetic acid, N,N-dimethylformamide.The described temperature eliminating reaction does not limits, preferably room temperature～150 DEG C.
In the above-mentioned methods, described substitution reaction can be carried out in the presence of a base.Described alkali is inorganic base or organic base；Preferably, described inorganic base is sodium hydroxide, potassium hydroxide, Strontium hydrate., Lithium hydrate, barium hydroxide, calcium hydroxide, Cesium hydrate., sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide or sodium hydrogen, described organic base be sodium alkoxide, potassium alcoholate, butyl lithium, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, quinoline, metal hydride, DMAP or organic amine, wherein, described sodium alkoxide is Feldalat NM, Sodium ethylate, sodium propoxide, sodium isopropylate, n-butyl alcohol sodium or sodium tert-butoxide；Described potassium alcoholate is Feldalat KM, potassium ethoxide, potassium propoxide, potassium isopropoxide, n-butyl alcohol potassium or potassium tert-butoxide, and described organic amine is triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine；More preferably, described inorganic base is sodium hydroxide, potassium hydroxide, Lithium hydrate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, sodium sulfide or sodium hydrogen, and described organic base is Feldalat NM, Sodium ethylate, potassium tert-butoxide, triethylamine, diethylamine, diisopropylamine or diisopropylethylamine.
Described substitution reaction can be carried out in a solvent, preferably, described solvent is selected from water, ether solvent (such as dimethyl ether, oxolane, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether), halogenated hydrocarbon (such as dichloromethane, dichloroethanes, chloroform, carbon tetrachloride), aromatic hydrocarbon solvent (such as benzene,toluene,xylene), C1～C5 lower alcohol (such as methanol, ethanol, isopropanol, butanol, the tert-butyl alcohol)；One or more in esters (such as ethyl acetate, methyl acetate), ketone (such as acetone, butanone), acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide.If necessary, it is also possible to add alkali-metal iodide, if sodium iodide, potassium iodide are as reaction promoter.
Present invention also offers following compound:
U's and Y is as defined above, and X is halogen, preferably bromine, chlorine, iodine.
Beneficial effect:
The invention provides a kind of new cloth auspicious piperazine azoles and salt, Aripiprazole and salt thereof or the preparation method of their key intermediate, the initiation material of the method is umbelliferone or 7-hydroxyl dehydrogenation coumarin, market can be supplied in a large number, cheap and easy to get, low cost, safety is high, easy and simple to handle, product yield is high, quality is good, is suitable for amplifying production.Particularly, using method of dehydrogenating to prepare in the method for cloth auspicious piperazine azoles, initiation material is compound 2c, and 2c is the intermediate of Aripiprazole, and market can be supplied in a large number, cheap and easy to get.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, professional and technical personnel in the field can be made to be more completely understood by the present invention, but limit the present invention never in any form.
The preparation of embodiment 1:7-neoprene epoxide coumarin
In reaction bulb, put into umbelliferone (500mg, 3.09mmol), potassium carbonate (640mg, 4.64mmol), 1-bromo-4-chlorobutane (426 μ l, 3.71mmol) and 10ml ethanol successively, be then heated to reflux 12h.After being removed by ethanol, adding water and make potassium carbonate dissolve, sucking filtration, filter cake 20ml petroleum ether washes twice.It is dried to obtain white product 606mg.
Embodiment 2: the preparation of compound IIa-1
7-neoprene epoxide coumarin (255mg is put into successively in reaction bulb, 1mmol), potassium carbonate (276,2mmol), sodium iodide (150,1mmol), 1-(benzothiophene-4-base) piperazine (218mg, 1mmol) with 10ml acetonitrile, then it is heated to reflux 24h.After acetonitrile is removed, add water and make potassium carbonate dissolve, sucking filtration, after filter cake is pulled an oar with 10ml acetonitrile, sucking filtration, it is dried to obtain product IIa-1 (380mg).
Embodiment 3: the preparation of cloth auspicious piperazine azoles
Being dissolved in methanolic ammonia solution by compound IIa-1, pressurization, 150 DEG C of heating, after having reacted, be spin-dried for, once, saturated aqueous sodium carbonate is washed once in washing, is dried get Bu Rui piperazine azoles.
Embodiment 4: the preparation of cloth auspicious piperazine azoles
Raw material 2a-1 (1g, 2.3mmol) is dissolved in dry 25ml dry tetrahydrofuran, is subsequently adding trifluoracetic acid (860 μ l, 11.5mmol), DDQ (2.08ml, 9.2mmol), then lower stirring at normal temperature 24h of nitrogen protection.After TLC display is reacted completely, adding 100ml water, furnishing alkalescence is 12 to pH, extracts with dichloromethane, and anhydrous sodium sulfate is dried, concentrating under reduced pressure, and products therefrom obtains sterling 750mg after purification through recrystallized from acetonitrile.
Embodiment 5: the preparation of cloth auspicious piperazine azoles
Raw material 2a-1 (1g, 2.3mmol) is dissolved in glacial acetic acid, adds bromine water, AcONa, be heated to 80 DEG C and react 24 hours.After TLC display reaction completely, adding a small amount of water, extract with dichloromethane, anhydrous sodium sulfate is dried, concentrating under reduced pressure, and products therefrom is through column chromatography get Bu Rui piperazine azoles sterling 750mg.
Embodiment 6: the preparation of Aripiprazole
With reference to the preparation method of embodiment 2,3 into, 1-(benzothiophene-4-base) piperazine is changed 2,3-Dichlorobenzene base-1-piperazine, it is substituted, aminating reaction obtains Aripiprazole.
Embodiment 7: the preparation (one kettle way) of cloth auspicious piperazine azoles
7-neoprene epoxide coumarin (255mg is put into successively in reaction bulb, 1mmol), potassium carbonate (276,2mmol), sodium iodide (150,1mmol), 1-(benzothiophene-4-base) piperazine (218mg, 1mmol) with DMF (10ml), then 85 DEG C of reacting by heating 24h.In reaction system, add ammonium acetate (770mg, 10mmol), be warming up to 150 DEG C of reaction 8h.Reactant liquor being cooled to room temperature, concentrating under reduced pressure solvent, adds dichloromethane, water extraction, saturated common salt is washed, and is dried, and concentrates, column chromatography get Bu Rui piperazine azoles (175mg, yield 40%).
Embodiment 8: the preparation (one kettle way) of cloth auspicious piperazine azoles
Take 7-(4-(4-(benzothiophene-4-base) piperazine-1-base) butoxy) chromane-2-one (436mg, 1mmol) and add ammonia methanol (3ml), pressurization, 150 DEG C of reaction 2h.It is cooled to room temperature, adds DDQ (3mmol), oxolane (3ml), under nitrogen protection, 24h is stirred at room temperature.Adding dichloromethane, water extraction, saturated common salt is washed, and anhydrous sodium sulfate is dried, and concentrates, column chromatography purification get Bu Rui piperazine azoles (160mg, yield 37%).
Embodiment 9: the preparation of cloth auspicious piperazine azoles
Compound 2c (1mmol) is put into successively in reaction bulb, potassium carbonate (276,2mmol), sodium iodide (150,1mmol), 1-(benzothiophene-4-base) piperazine (218mg, 1mmol) and acetonitrile (10ml), be then heated to reflux 24h.After TLC detection reaction completely, concentrating under reduced pressure solvent, add water, stirring, filter, screening recrystallized from acetonitrile, sucking filtration, obtain compound 2a-1, direct plunge into next step without being further purified.
By the method for compound 2a-1 reference embodiment 4 by DDQ dehydrogenation, obtain object cloth auspicious piperazine azoles.
Embodiment 10: the preparation of cloth auspicious piperazine azoles
By compound 2c (30g, 100.67mmol), DDQ (25.1g, 110.57mmol) joins in 1L reaction bulb, add 1,4-dioxane 300mL, stirs 2 hours at 95 DEG C, and TLC monitoring reaction terminates, concentrating under reduced pressure, add frozen water, add sodium thiosulfate solution, stirring, add the extraction of 3L dichloromethane, separating organic layer, organic layer saturated aqueous common salt washs, and anhydrous slufuric acid acid sodium is dried, filter, it is concentrated to give 29.6g faint yellow solid 1c, the most quantitative yield, direct plunges into next step without being further purified.
By compound 1c (17.5g, 59.12mmol), 1-(benzothiophene-4-base) piperazine hydrochloride (17.3g, 67.98mmol), potassium carbonate (20.7g, 150mmol), sodium iodide (1.33g, 8.87mmol) join in reaction bulb, add 500mL acetonitrile, back flow reaction, after TLC detection reaction terminates, concentrating under reduced pressure solvent, add water making beating, filter, filter cake is washed, and crude product with recrystallized from acetonitrile, filters again, it is dried, obtain white solid 21g, i.e. object cloth auspicious piperazine azoles (1a-1), HPLC purity > 99%.
Claims (17)
1. preparing cloth auspicious piperazine azoles and salt, Aripiprazole and salt thereof, cloth auspicious piperazine azoles and a method for aripiprazole intermediate, described method is one of following method:
Method one: being prepared compound I or its salt by compound II or its salt through aminating reaction, reaction equation is as follows:
Wherein, Z is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl
Represent singly-bound or double bond；
Or
Method two: being prepared compound 1 or its salt by compound 2 or its salt through dehydrogenation reaction, reaction equation is as follows:
Wherein, U is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl
Y is O or NH,
Condition is, when U is Br or 2, during 3-Dichlorobenzene base-1-piperazinyl, and when carrying out dehydrogenation reaction under oxidant existence condition, Y is not NH.
Method the most according to claim 1, wherein,
In method two, described dehydrogenation reaction is carried out as follows:
The dehydrogenation under oxidant existence condition of compound 2 or its salt obtains compound 1 or its salt, or
Compound 2 or its salt obtain intermediate 3 or its salt by halogenating reaction, then are reacted by elimination and prepare compound 1 or its salt, and reaction equation is as follows:
Wherein, X is halogen (preferably Cl, Br, iodine).
Method the most according to claim 1, wherein,
Described method one is carried out as follows:
Compound IIb or its salt carrying out dehydrogenation reaction and obtains compound IIa or its salt, then carry out aminating reaction and obtain compound Ia, reaction equation is as follows:
Or
Compound IIb or its salt carrying out aminating reaction and obtains compound Ib or its salt, then carry out dehydrogenation reaction and obtain compound Ia or its salt, reaction equation is as follows
Wherein, Za is 1 (benzothiophene 4 base) piperazinyl or 2,3 Dichlorobenzene base 1 piperazinyls；
Or
Described method two is carried out as follows:
Compound 2b or its salt carrying out aminating reaction and obtains compound 2a or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows:
Or
Compound 2b or its salt carrying out dehydrogenation reaction and obtains compound 1b or its salt, then carry out aminating reaction and obtain compound 1a or its salt, reaction equation is as follows:
Wherein, Ua is 1 (benzothiophene 4 base) piperazinyl or 2,3 Dichlorobenzene base 1 piperazinyls.
Method the most according to claim 1, wherein,
Described method one is carried out as follows:
Compound IIc, IId or its salt being carried out substitution reaction obtain compound IIa, IIb or its salt with compound IV or its salt, then carry out aminating reaction and obtain compound Ia, Ib or its salt, reaction equation is as follows:
Or
Compound IIc, IId or its salt carrying out aminating reaction and obtains compound Ic, Id or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ia, Ib or its salt, reaction equation is as follows:
Wherein, Zc is halogen (preferably Cl, Br) or other leaving groups (are i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen；
R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
Za is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl；
Represent singly-bound or double bond, wherein, in compound IIa, IIc, Ia and Ic,For double bond, in compound IIb, IId, Ib and Id,For singly-bound；
Or
Described method two is carried out as follows:
Compound 2c, 2d or its salt being carried out substitution reaction obtain compound 2a, 2b or its salt with compound IV or its salt, then carry out dehydrogenation reaction and obtain compound 1a, 1b or its salt, reaction equation is as follows:
Or
Compound 2c, 2d or its salt carrying out dehydrogenation reaction and obtains compound 1c, 1d or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1a, 1b or its salt, reaction equation is as follows:
Wherein, Uc is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen)；
R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
Ua is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl；
Y is O or NH, and wherein, in compound 2a, 2c, 1a and 1c, Y is NH, and in compound 2b, 2d, 1b and 1d, Y is O；
Condition is, when Uc is Br or 2, during 3-Dichlorobenzene base-1-piperazinyl, and when being reaction under oxidant existence condition, Y is not NH.
Method the most according to claim 1, wherein,
Described method one is carried out as follows:
Compound IIc or its salt being carried out substitution reaction obtain compound IIa or its salt with compound IV or its salt, then carry out aminating reaction and obtain compound Ia or its salt, reaction equation is as follows:
Or
Compound IIc or its salt carrying out aminating reaction and obtains compound Ic or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ia or its salt, reaction equation is as follows:
Or
Compound IId or its salt carrying out dehydrogenation reaction and obtains compound IIc or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound IIa or its salt, then carry out aminating reaction and obtain compound Ia or its salt, reaction equation is as follows:
Or
Compound IId or its salt being carried out substitution reaction obtain compound IIb or its salt with compound IV or its salt, then carry out dehydrogenation reaction and obtain compound IIa or its salt, then carry out aminating reaction and obtain compound Ia or its salt, reaction equation is as follows:
Or
Compound IId or its salt carrying out aminating reaction and obtains compound Id or its salt, then carry out dehydrogenation reaction and obtain compound Ic or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ia or its salt, reaction equation is as follows:
Or
Compound IId or its salt carrying out aminating reaction and obtains compound Id or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound Ib or its salt, then carry out dehydrogenation reaction and obtain compound Ia or its salt, reaction equation is as follows:
Wherein, Zc is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen)；
R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
Za is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl；
Or
Described method two is carried out as follows:
Compound 2c or its salt and compound IV or its salt carrying out substitution reaction and obtains compound 2a or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows:
Or
Compound 2c or its salt carrying out dehydrogenation reaction and obtains compound 1c or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1a or its salt, reaction equation is as follows:
Or
Compound 2d or its salt carrying out aminating reaction and obtains compound 1d or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1b or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows:
Or
Compound 2d or its salt being carried out substitution reaction obtain compound 2b or its salt with compound IV or its salt, then carry out aminating reaction and obtain compound 2a or its salt, then carry out dehydrogenation reaction and obtain compound 1a or its salt, reaction equation is as follows:
Or
Compound 2d or its salt carrying out dehydrogenation reaction and obtains compound 1d or its salt, then carry out aminating reaction and obtain compound 1c or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1a compound or its salt, reaction equation is as follows:
Or
Compound 2d or its salt carrying out dehydrogenation reaction and obtains compound 1d or its salt, then carry out substitution reaction with compound IV or its salt and obtain compound 1b or its salt, then carry out aminating reaction and obtain compound 1a or its salt, reaction equation is as follows:
Wherein, Uc is halogen (preferably Cl, Br) or other leaving groups (are i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen；
R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
Ua is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl.
6. according to the method described in claim 4 or 5, wherein,
In described method one, compound IIc and IId is substituted reaction in the presence of a base and prepares by compound III with compound VI or its salt:
In described method two, compound 2c and 2d is substituted reaction in the presence of a base and prepares by compound 4 with compound VI or its salt:
Wherein, X1For halogen or other leaving groups (being i.e. similar to the group that can cause substitution reaction of halogen)；It is preferably Cl, Br, OH, OMs, OTf or p-toluenesulfonyl (OTs),
Zc and Uc is each independently halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen)；
Represent singly-bound or double bond,
Y is O or NH,
Zc and Uc and X1Identical or different.
7. according to the method according to any one of claim 2-5, wherein, the reaction of described each step is carried out according to one kettle way.
8. one kettle way prepares cloth auspicious piperazine azoles or its salt or Aripiprazole or a method for its salt, and its reaction equation is as follows,
Described method includes:
(1) make compound IIc and compound IV or its salt carry out substitution reaction and generate compound IIa；
(2) state directly up and reaction system adds amination reagent carry out aminating reaction and obtain compound Ia or its salt；
Wherein, Zc is halogen (preferably Cl, Br) or other leaving groups (are i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen；
R1And R2It is all Cl, or R1And R2Benzothienyl is constituted together with coupled phenyl ring；
Za is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl.
9. one kettle way prepares cloth auspicious piperazine azoles or a method for its salt, as shown in formulas below,
The method comprises the following steps:
(1) compound 2c and compound IV-1 or its salt generation substitution reaction is made to generate compound 2a-1；
(2) state directly up and reaction system adds dehydrating agent carry out dehydrogenation reaction and obtain compound 1a-1 or its salt；
Wherein, Uc is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen),
Ua is 1-(benzothiophene-4-base) piperazinyl.
10. one kettle way prepares cloth auspicious piperazine azoles or a method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) make compound 2c carry out dehydrogenation reaction and obtain compound 1c；
(2) state addition compound IV-1 or its salt generation substitution reaction in reaction system directly up and obtain compound 1a-1 or its salt；
Wherein, Uc be halogen (preferably Cl, Br) or other leaving groups (be i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen,
Ua is 1-(benzothiophene-4-base) piperazinyl.
11. 1 kinds of one kettle ways prepare cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) compound IId and compound IV-1 or its salt generation substitution reaction is made to generate compound IIb-1；
(2) state addition dehydrating agent in reaction system directly up and carry out dehydrogenation reaction generation compound IIa-1；
(3) state directly up and reaction system adds amination reagent carry out aminating reaction and obtain compound Ia-1 or its salt；
Wherein, Zc be halogen (preferably Cl, Br) or other leaving groups (be i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen,
Za is 1-(benzothiophene-4-base) piperazinyl.
12. 1 kinds of one kettle ways prepare cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) compound 2d and compound IV-1 or its salt generation substitution reaction is made to generate compound 2b-1；
(2) state addition amination reagent in reaction system directly up and carry out aminating reaction generation compound 2a-1；
(3) state directly up and reaction system adds dehydrating agent carry out dehydrogenation reaction and obtain compound 1a-1 or its salt；
Wherein, Uc be halogen (preferably Cl, Br) or other leaving groups (be i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen,
Ua is 1-(benzothiophene-4-base) piperazinyl.
13. 1 kinds of one kettle ways prepare cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
Described method includes:
(1) compound 2c and compound IV or its salt generation substitution reaction is made to generate compound 2a；
(2) state directly up and reaction system adds halide reagent carry out halogenating reaction and obtain compound 3a or its salt；
(3) compound 3a or its salt carry out eliminating reaction in the presence of with or without alkali and obtain cloth auspicious piperazine azoles or its salt or OPC-14857 or its salt；
Wherein, Uc be halogen (preferably Cl, Br) or other leaving groups (be i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen,
Ua is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl,
X is bromine, chlorine, iodine.
14. 1 kinds of one kettle ways prepare cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
Described method includes:
(1) in compound 2c, addition halide reagent carries out halogenating reaction and obtains compound 3c or its salt；
(2) compound 3c or its salt carry out eliminating reaction in the presence of with or without alkali and obtain compound 1c；
(3) state directly up and reaction system adds compound IV or its salt generation substitution reaction generation compound 1a；
Wherein, Uc be halogen (preferably Cl, Br) or other leaving groups (be i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen,
Ua is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl,
X is bromine, chlorine, iodine.
15. 1 kinds of one kettle ways prepare cloth auspicious piperazine azoles or the method for its salt, as shown in formulas below:
The method comprises the following steps:
(1) compound 2d and compound IV or its salt generation substitution reaction is made to generate compound 2b；
(2) state addition halide reagent in reaction system directly up and carry out halogenating reaction generation compound 3a；
(3) compound 3a directly carries out eliminating reacting generating compound 1b in the presence of with or without alkali；
(4) state directly up and reaction system adds amination reagent carry out aminating reaction and obtain cloth auspicious piperazine azoles or its salt or OPC-14857 or its salt；
Wherein, Uc is halogen (preferably Cl, Br) or other leaving groups,
X be bromine, chlorine, iodine (be i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen,
Ua is 1-(benzothiophene-4-base) piperazinyl or 2,3-Dichlorobenzene base-1-piperazinyl.
16. according to the method according to any one of claim 1-15, wherein,
Described aminating reaction is carried out in the presence of amination reagent；One or more in ammonia, carbamide, ammonium acetate, ammonium chloride, ammonium formate, ammonia of described amination reagent；Preferably, described amination reagent is ammonia, ammonia or ammonium acetate；And/or
Described aminating reaction can be carried out in water or nonaqueous solvent, it is also possible to solubilizer is not carried out；Preferably, described solvent is selected from water, C1～C5 lower alcohol, N, one or more in dinethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide, acetonitrile, described C1～C5 lower alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propylene glycol or glycerol；It is highly preferred that described solvent is one or more in water, methanol, ethanol, DMF, dimethyl sulfoxide, hexamethyl phosphoramide, acetonitrile；And/or
In described method of dehydrogenating, described reaction under oxidant existence condition；Described oxidant is selected from O2、Br2、H2O2、MnO2, 2,3-bis-chloro-5,6-dicyan 1,4-benzoquinone, H2NOH-HCl、NBS、NaI、AlCl3、PhSeCl、BuLi、Me3SiN=CMeOSiMe3, EtN=C=N (CH2)3NMe2, it is also possible to add azodiisobutyronitrile (AIBN), Pd (OAc)2、t-Bu3P、AcOH、AcONa、K2CO3、(PhCO2)2、EtN(Pr-i)2；The reaction dissolvent of described dehydrogenation reaction is water or nonaqueous solvent, and described nonaqueous solvent is selected from dioxane, Carbon bisulfide, acetic acid, DMF, alkyl halide, ethers, DMF, DMSO, aromatic hydrocarbon solvent；
Described substitution reaction is carried out the most in a solvent；Described alkali is inorganic base or organic base；Preferably, described inorganic base is sodium hydroxide, potassium hydroxide, Strontium hydrate., Lithium hydrate, barium hydroxide, calcium hydroxide, Cesium hydrate., sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide or sodium hydrogen, described organic base be sodium alkoxide, potassium alcoholate, butyl lithium, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, quinoline, metal hydride, DMAP or organic amine, wherein, described sodium alkoxide is Feldalat NM, Sodium ethylate, sodium propoxide, sodium isopropylate, n-butyl alcohol sodium or sodium tert-butoxide；Described potassium alcoholate is Feldalat KM, potassium ethoxide, potassium propoxide, potassium isopropoxide, n-butyl alcohol potassium or potassium tert-butoxide, and described organic amine is triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine；More preferably, described inorganic base is sodium hydroxide, potassium hydroxide, Lithium hydrate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, sodium sulfide or sodium hydrogen, and described organic base is Feldalat NM, Sodium ethylate, potassium tert-butoxide, triethylamine, diethylamine, diisopropylamine or diisopropylethylamine；Described solvent is selected from water, ether solvent, halogenated hydrocarbon, aromatic hydrocarbon solvent, C1～C5 lower alcohol；One or more in esters, ketone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide；
Described halogenating reaction is carried out in the presence of halogenating agent in a solvent, and described halogenating agent is selected from Br2、I2、Cl2、PCl5、SO2Cl2, described solvent be one or more in oxolane, carbon tetrachloride, ethyl acetate, acetic acid, chloroform, ethanol, dioxane, N,N-dimethylformamide, benzene；And/or
Described elimination reaction is carried out in the presence of with or without alkali in a solvent；Described alkali is inorganic base or organic base；Preferably, described inorganic base is sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, described organic base is 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, quinoline, metal hydride, DMAP or organic amine, wherein, described organic amine is triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine；It is highly preferred that described inorganic base is sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, sodium sulfide or sodium hydrogen, described organic base is triethylamine, diethylamine, diisopropylamine or diisopropylethylamine；Described solvent is selected from water, ether solvent, halogenated hydrocarbon, aromatic hydrocarbon solvent, C1～C5 lower alcohol；One or more in esters, ketone, acetic acid, N,N-dimethylformamide.
17. following compound:
Wherein, U is halogen (preferably Cl, Br) or other leaving groups (being i.e. similar to the group (preferably OH, OMs, OTf, p-toluenesulfonyl OTs) that can cause substitution reaction of halogen), 1-(benzothiophene-4-base) piperazinyl or 2; 3-Dichlorobenzene base-1-piperazinyl
Y is O or NH,
X is halogen, preferably bromine, chlorine, iodine.
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| CN105399736A (en) * | 2016-01-07 | 2016-03-16 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method of brexpiprazole |
| CN106645494A (en) * | 2016-12-29 | 2017-05-10 | 成都百裕制药股份有限公司 | Detection method of brexpiprazole starting material related substances |
| CN106632291A (en) * | 2016-10-09 | 2017-05-10 | 瑞阳制药有限公司 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
| US10358440B2 (en) | 2016-05-03 | 2019-07-23 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| CN114166960A (en) * | 2021-11-10 | 2022-03-11 | 西安远大科创医药科技有限公司 | Detection method of brexpiprazole related substance |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105399736A (en) * | 2016-01-07 | 2016-03-16 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method of brexpiprazole |
| US10358440B2 (en) | 2016-05-03 | 2019-07-23 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| CN106632291A (en) * | 2016-10-09 | 2017-05-10 | 瑞阳制药有限公司 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
| CN106645494A (en) * | 2016-12-29 | 2017-05-10 | 成都百裕制药股份有限公司 | Detection method of brexpiprazole starting material related substances |
| CN106645494B (en) * | 2016-12-29 | 2019-09-06 | 成都百裕制药股份有限公司 | According to a detection method of the piperazine azoles starting material in relation to substance |
| CN114166960A (en) * | 2021-11-10 | 2022-03-11 | 西安远大科创医药科技有限公司 | Detection method of brexpiprazole related substance |
| CN114166960B (en) * | 2021-11-10 | 2023-09-29 | 西安远大科创医药科技有限公司 | Method for detecting substances related to epipiprazole |
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