CN109456253A - A kind of method of chiral induction synthesis (S) -3- (4- bromophenyl)-piperidines or its salt - Google Patents

A kind of method of chiral induction synthesis (S) -3- (4- bromophenyl)-piperidines or its salt Download PDF

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CN109456253A
CN109456253A CN201910026141.3A CN201910026141A CN109456253A CN 109456253 A CN109456253 A CN 109456253A CN 201910026141 A CN201910026141 A CN 201910026141A CN 109456253 A CN109456253 A CN 109456253A
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compound
reaction
product
bromophenyl
piperidines
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CN109456253B (en
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赖亮
冯亚兵
郭朋
朱文峰
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Shanghai Bo Pu Connaught Technology Development Co Ltd
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Shanghai Bo Pu Connaught Technology Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

Abstract

The present invention relates to the methods of a kind of chiral induction synthesis (S) -3- (4- bromophenyl)-piperidines or its salt.Specifically, method of the invention is using original -4- bromo-acid trimethyl and (S)-(-)-t-butyl sulfonamide as starting material, it is successively condensed, replaced, being restored, after cyclization and the reaction such as slough chiral auxiliary, available (S) -3- (4- bromophenyl)-piperidines or its salt.Wherein, the single diastereoisomer of high-purity can be obtained after reduction reaction by recrystallization.The single diastereoisomer of high-purity can be further obtained after ring closure reaction by recrystallization.Method raw material of the invention is cheap and easy to get, and easy to operate, high income is at low cost, is suitble to industrialized production.

Description

A kind of method of chiral induction synthesis (S) -3- (4- bromophenyl)-piperidines or its salt
Technical field
The invention belongs to the synthesis fields of medicine intermediate, in particular it relates to a kind of chiral induction synthesis (S)- The method of 3- (4- bromophenyl)-piperidines or its salt.
Background technique
With the variation of human habitat, living standard and life style and the progress of medicine, spectrum of disease is had occurred Significant change.General sexually transmitted disease is gradually controlled, and cancer then becomes increasingly common and seriously threatens human life and Sheng One of the important diseases of bioplasm amount.The second largest reason for leading to human death is had become in China or even the whole world, cancer at present. In recent years, the essence for constantly illustrating tumour of molecular weight tumor and molecular pharmacology, malignant tumour is that body own cells become The disease of uncontrolled proliferation and diffusion, is a kind of cell Proliferation, the disease of disdifferentiation.
Ni Lapani (Niraparib, 2- [4- ((3S) -3- piperidyl) phenyl] -2H- indazole -7- formamide, such as following formula It is shown), belong to PARP inhibitor, this is a kind of targeted drug for being directed to PARP gene, is mainly used for BRCA1/2 gene mutation Patient, target spot is clear, meets the accurate medical therapy of cancer, it is the relevant ovum of BRCA gene mutation that Ni Lapani submits indication in advance Nest cancer, breast cancer, it should can be the PARP inhibitor of second listing.Last year AstraZeneca has had listed that PARP inhibitor is difficult to understand La Pani (Olaparib is also Lynparza) is approved for the oophoroma of BRCA mutation because of its significant effect, sells peak Value is expected to reach annual 2000000000 dollars or more.
Currently, the method for synthesizing Ni Lapani, mainly using 4- (3S) -3- piperidyl-aniline as raw material.For example, It is reported in J.Med.Chem.2009,52,7170-7185 and Org.Process Res.Dev.2011,15,831-840 following Synthetic route:
Although this route synthetic route is short, it has the shortcomings that obvious.Firstly, starting material 4- iodonitrobenzene and 3- pyrrole Pyridine boric acid is expensive, is not easy largely to obtain；Secondly, having used the catalysis such as expensive triphenylphosphine palladium and platinum oxide in route Agent, hydrogenation pressure are larger, it is difficult to industrialize；Again, chemical resolution has been used in route and obtained single enantiomer, need to weigh three times Crystallization can just obtain qualified enantiomer, and efficiency is very low；Moreover, having used dangerously explosive sodium azide in route, and should The reaction temperature of step is higher, and operational danger is very big.
2014, larger improvement is proposed to synthetic route in Org.Process Res.Dev.2014,18,215-227, It is specific as follows:
It has used intermediate (S) -3- (4- bromophenyl)-piperidines to synthesize for Ni Lapani for the first time, has avoided using nitrine Change sodium, but this routine synthetic steps is long, and (such as raw material dosage is big, cumbersome and complicated, generation there are also many places technical problem The three wastes are big etc.) have it is to be solved.
Summary of the invention
Aiming at the shortcomings in the prior art, the purpose of the present invention is to provide a kind of new (S) -3- (4- bromophenyl)-piperazines The synthetic method of pyridine or its salt.
In order to realize the purpose, the present invention provides following technical schemes:
The present invention provides the synthetic methods of one kind (S) -3- (4- bromophenyl)-piperidines or its salt, comprising steps of
(1) under solvent-free conditions, in the presence of a catalyst, compound 1 and (S)-(-)-t-butyl sulfonamide carry out Reaction mixture is concentrated after reaction for condensation reaction, concentrate is collected, to obtain compound 2 or contain chemical combination The product of object 2；
(2) in atent solvent, in the presence of a base, the compound 2 that step (1) is obtained or the product containing compound 2 Substitution reaction is carried out with the chloro- 3- iodopropane of 1-, to obtain compound 3 or the product containing compound 3；
(3) in atent solvent, in the presence of reducing agent and catalyst, compound 3 that step (2) is obtained or containing changing The product for closing object 3 carries out reduction reaction, to obtain compound 4；
(4) in atent solvent, in the presence of a base, compound 4 is subjected to ring closure reaction, to obtain compound 5；
(5) in atent solvent, in the presence of hydrogen chloride, compound 5 is carried out to slough chiral auxiliary reaction, thus Obtain compound 6；
In another preferred example, after the step (5), further include alkalinization step: compound 6 is alkalized, thus Obtain (S) -3- (4- bromophenyl)-piperidines.
In another preferred example, in step (1), the condition of the concentration is that pressure is 0.5 millimetres of mercury and/or temperature is 60~100 degree.
In another preferred example, in step (1), the catalyst can be p-methyl benzenesulfonic acid.
In another preferred example, in step (1), the molar ratio of catalyst and compound 1 is 0.01~0.10, preferably 0.02。
In another preferred example, in step (1), the molar ratio of (S)-(-)-t-butyl sulfonamide and compound 1 is 0.5 ~3.0, preferably 0.8.
In another preferred example, in step (1), the reaction temperature of the condensation reaction is 70~120 degree, preferably 95 ~100 degree.
In another preferred example, compound 3 ' is contained in the compound 3 that step (2) obtains or the product containing compound 3；
In another preferred example, compound 3 ' is contained in the compound 3 that step (2) obtains or the product containing compound 3； Wherein, the purity of compound 3 is more than 60%；Preferably, the purity of compound 3 is 60%~70%.
In another preferred example, in step (2), the alkali is LiHMDS or KHMDS.
In another preferred example, in step (2), the molar ratio of alkali and compound 2 is 1.0~4.0, preferably 2.0.
In another preferred example, in step (2), the molar ratio of the chloro- 3- iodopropane of 1- and compound 2 is 0.8~2.0, excellent It is selected as 1.3.
In another preferred example, in step (2), the reaction temperature of the substitution reaction is -78~0 degree, preferably -70 ~-65 degree.
In another preferred example, the compound 3 that step (2) obtains or the product containing compound 3 terminate for substitution reaction The crude product obtained afterwards, the crude product are directly used in subsequent reactions.
In another preferred example, the crude product obtained after the substitution reaction is obtained by following steps: being replaced After reaction, by reaction mixture after being quenched and extracting, organic phase is collected；Then by organic phase through washing, drying and After concentration, the crude product is obtained.
In another preferred example, described be quenched is quenched using aqueous ammonium chloride solution.
In another preferred example, the extraction is extracted using ethyl acetate.
In another preferred example, the washing uses saturated common salt water washing.
In another preferred example, the compound 4 that step (3) obtains be after reduction reaction obtained crude product by knot The product that crystalline substance obtains after purification.
In another preferred example, in the product obtained after crystallization purifying, purity >=90% of obtained compound 4.
In another preferred example, the crude product obtained after the reduction reaction is obtained by following steps: reduction After reaction, by reaction mixture after being quenched and extracting, organic phase is collected；Then by organic phase through washing, drying and Concentration, obtains the crude product.
In another preferred example, described be quenched is quenched using saturated sodium bicarbonate aqueous solution.
In another preferred example, the extraction is extracted using ethyl acetate.
In another preferred example, the washing uses saturated common salt water washing.
In another preferred example, the solvent for crystallizing use is selected from the group: methanol, ethyl alcohol, acetonitrile, acetone, ethyl acetate, just Heptane, n-hexane, petroleum ether or combinations thereof.
In another preferred example, the solvent used is crystallized as normal heptane.
In another preferred example, the temperature used is crystallized as -20~30 degree.
In another preferred example, the temperature used is crystallized as 20~25 degree.
In another preferred example, in step (3), the reducing agent is sodium borohydride.
In another preferred example, in step (3), the molar ratio of reducing agent and compound 3 is 1~10, preferably 5.
In another preferred example, in step (3), the catalyst is methanol.
In another preferred example, in step (3), the temperature of reduction reaction is 25~70 degree, preferably 65~70 degree.
In another preferred example, the compound 5 that step (4) obtains be after ring closure reaction obtained crude product by knot The product that crystalline substance obtains after purification.
In another preferred example, in the product obtained after crystallization purifying, purity >=98% of obtained compound 5.
In another preferred example, the crude product obtained after the ring closure reaction is obtained by following steps: cyclization After reaction, by reaction mixture after being quenched and extracting, organic phase is collected；Then by organic phase through washing, drying and Concentration, obtains the crude product.
In another preferred example, described be quenched is quenched using aqueous ammonium chloride solution.
In another preferred example, the extraction is extracted using ethyl acetate.
In another preferred example, the washing uses saturated common salt water washing.
In another preferred example, the solvent for crystallizing use is selected from the group: methanol, ethyl alcohol, acetonitrile, acetone, ethyl acetate, just Heptane, n-hexane, petroleum ether or combinations thereof.
In another preferred example, the solvent used is crystallized as normal heptane.
In another preferred example, the temperature used is crystallized as -20~30 degree.
In another preferred example, the temperature used is crystallized as 20~25 degree.
In another preferred example, in step (4), the alkali is sodium hydride.
In another preferred example, in step (4), the molar ratio of alkali and compound 4 is 1~10, preferably 3.
In another preferred example, in step (4), the temperature of ring closure reaction is 25~100 degree, preferably 80~85 degree.
In another preferred example, in step (5), the molar ratio of hydrogen chloride and compound 5 is 1~20, preferably 5.
In another preferred example, in step (5), hydrogen chloride uses hydrogen chloride solution form.
In another preferred example, in step (5), the mass concentration of hydrogen chloride in the solution is 10%~40%, preferably 30%.
In another preferred example, in step (5), hydrogen chloride solution is hydrogen chloride dioxane solution, chlorination hydroacetic acid second Ester solution, ethanol solution of hydrogen chloride, hydrogen chloride methanol solution or hydrogen chloride tetrahydrofuran solution；Preferably ethanolic hydrogen chloride is molten Liquid.
In another preferred example, described to slough chiral auxiliary after reaction in step (5), by reaction mixture It is filtered, directly obtains compound 6.
The present invention also provides the midbody compounds 4 for being used to prepare (S) -3- (4- bromophenyl)-piperidines or its salt；
The present invention also provides the systems for the midbody compound 4 for being used to prepare (S) -3- (4- bromophenyl)-piperidines or its salt Preparation Method, comprising steps of
(1) under solvent-free conditions, in the presence of a catalyst, compound 1 and (S)-(-)-t-butyl sulfonamide carry out Reaction mixture is concentrated after reaction for condensation reaction, concentrate is collected, to obtain compound 2 or contain chemical combination The product of object 2；
(2) in atent solvent, in the presence of a base, the compound 2 that step (1) is obtained or the product containing compound 2 Substitution reaction is carried out with the chloro- 3- iodopropane of 1-, to obtain compound 3 or the product containing compound 3；
(3) in atent solvent, in the presence of reducing agent and catalyst, compound 3 that step (2) is obtained or containing changing The product for closing object 3 carries out reduction reaction, to obtain compound 4；
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific embodiment
The present inventor is after extensive and in-depth study, it has unexpectedly been found that a kind of chiral induction synthesizes (S) -3- (4- bromine Phenyl)-piperidines or its salt method.On this basis, the present invention is completed.
Intermediate (S) -3- (4- the aminocarbonyl phenyl)-piperidines used earliest compared to the prior art, the Buddhist nun that the present invention synthesizes Novel bromine segment intermediate (S) -3- (4- the bromophenyl)-piperidines of La Pani has incomparable advantage, is synthesis Ni Lapani Most potential intermediate.Using intermediate (S) -3- (4- bromophenyl)-piperidines, raw material in former preparation process can be overcome and urged Agent is expensive, avoids that high explosive sodium azide is hydrogenated and used using elevated pressurization, to reduce to industrialized production equipment With the requirement of safety etc..
In existing method, preparation (S) -3- (4- bromophenyl)-piperidines uses enzymatic synthesis method, but closes in this method It is longer at step, and raw material dosage is big, operation is extremely cumbersome and complicated, has thus also produced raw a large amount of three wastes.Present invention employs Chiral induction synthetic method prepares (S) -3- (4- bromophenyl)-piperidines, and the enzymatic that method of the invention uses than existing methods is closed There is greater advantage at method.It, can be with the invention proposes synthesizing (S) -3- (4- bromophenyl)-piperidines using chiral shift reagent Form the diastereoisomer of differentiation, the problems such as poor efficiency of chemical resolution can be overcome.
In (S) -3- (4- bromophenyl)-piperidines of the present invention or its salt, the salt is hydrochloride.
The present invention provides the preparation methods of one kind (S) -3- (4- bromophenyl)-piperidines or its salt, and this method includes following Step (1)-(6).
Step (1): under solvent-free conditions, in the presence of a catalyst, compound 1 and (S)-(-)-t-butyl sulfonamide It carries out condensation reaction reaction mixture is concentrated after reaction, concentrate is collected, to obtain compound 2 or contain The product of compound 2；
In step (1), the effect of the concentration is generally removed unreacted by-product (methanol), recycles raw material compound 1 (original -4- bromo-acid trimethyl).The concentration is preferably concentrated under reduced pressure.The pressure of the reduced pressure is preferably 0.5 Millimetres of mercury.The temperature of concentration is preferably 60~100 degree, and more preferable 70~75 degree.
In step (1), the condensation reaction is solvent-free reaction.
In step (1), the catalyst can be conventional use of catalyst in such reaction of this field, preferably to toluene Sulfonic acid.The dosage of the catalyst can generally be catalyzed such reaction and carry out.The molar ratio of catalyst and compound 1 is excellent Select 0.01~0.10, more preferable 0.02.
In step (1), the molar ratio of (S)-(-)-t-butyl sulfonamide and compound 1 is referred to the routine of this field It is selected, preferably 0.5~3.0, more preferable 0.8.
In step (1), the routine that the reaction temperature of the condensation reaction can refer to such reaction of this field is selected, It is preferred that 70~120 degree, more preferable 95~100 degree.
In step (1), the reaction process of the condensation reaction can using in this field traditional test methods (such as TLC, HPLC or NMR) it is monitored, as the terminal of reaction when generally being disappeared using compound (S)-(-)-t-butyl sulfonamide. The time of the condensation reaction preferably 2~6 hours.
Step (2): in atent solvent, in the presence of a base, compound 2 that step (1) is obtained or containing compound 2 Product and the chloro- 3- iodopropane of 1- carry out substitution reaction, to obtain compound 3 or the product containing compound 3；
The compound 2 that the step (1) obtains or the product containing compound 2 are that obtained concentration is collected in step (1) Object.
Contain compound 3 ' in the compound 3 that step (2) obtains or the product containing compound 3.Wherein, compound 3 Purity is more than 60%；Preferably, the purity of compound 3 is 60%~70%.
In step (2), the alkali can react conventional use of alkali, preferably LiHMDS for such in this field.
In step (2), the routine that the molar ratio of the alkali and compound 2 is referred to this field is selected, preferably 1.0~4.0, more preferable 2.0.
In step (2), the routine that the molar ratio of the chloro- 3- iodopropane of 1- and compound 2 is referred to this field is selected, It is preferred that 0.8~2.0, more preferable 1.3.
In step (2), the routine that the reaction temperature of the substitution reaction can refer to such reaction of this field is selected, It is preferred that -78~0 degree, more preferably -70~-65 degree.
In step (2), the atent solvent that the substitution reaction uses can be conventional use of for such reaction in this field Organic solvent, preferably THF.
In step (2), the atent solvent can react normal with the volume mass of compound 2 ratio for such in this field Rule, preferably 5~15, more preferable 10.
In step (2), after the concentrate that step (1) obtains generally is down to reaction temperature (such as -65 degree), then 1- is added dropwise Chloro- 3- iodopropane.The time for adding of the chloro- 3- iodopropane of 1- preferably 0.5~2 hour, more preferable 1 hour.
In step (2), the reaction process of the substitution reaction can using in this field traditional test methods (such as TLC, HPLC or NMR) it is monitored, as the terminal of reaction when generally being disappeared using compound 2.The time of the substitution reaction is excellent It selects 2~10 hours, more preferable 2 hours.
In step (2), the crude product obtained after substitution reaction is used for subsequent reactions or straight after using column Chromatographic purification It connects for subsequent reactions.
In step (2), the crude product obtained after substitution reaction is obtained by following steps: after substitution reaction, By reaction mixture after being quenched and extracting, organic phase is collected；Then, it is obtained after organic phase being washed, dried and concentrated Crude product.
Step (3): in atent solvent, in the presence of reducing agent and catalyst, compound 3 that step (2) is obtained or Product containing compound 3 carries out reduction reaction, to obtain compound 4；
The compound 3 that the step (2) obtains or the product containing compound 3 are in step (2) after substitution reaction Obtained crude product.
In step (3), the reducing agent can react conventional use of reducing agent, preferably hydroboration for such in this field Sodium.
In step (3), the molar ratio of reducing agent and compound 3 is referred to this field and is routinely selected, preferably 1~ 10, more preferable 5.The reducing agent can be added at one time.
In step (3), the reaction temperature of the reduction reaction is preferably 25~70 degree, and more preferable 65~70 degree.
In step (3), the atent solvent that the reduction reaction uses routinely is selected referring to this field, preferably THF, DMF, DCM, more preferable THF.The volume mass ratio of the atent solvent and compound 3 is referred to this field and routinely carries out, excellent Select 1~10, more preferable 8.
In step (3), the reaction process of the reduction reaction can using in this field traditional test methods (such as TLC, HPLC or NMR) it is monitored, as the terminal of reaction when generally being disappeared using compound 3.The reaction time of the reduction reaction It is preferred that 0.5~5 hour.
In step (3), the catalyst is methanol.Methanol uses dropwise addition mode.Time for adding preferably 0.2~1 hour, more It is preferred that 0.5 hour.Dropping temperature is referred to the routine that such in this field reacts and is selected, and preferably 0~30 degree, more preferably 20~25 degree.
In step (3), compound 4 that the crude product that obtains after reduction reaction uses crystallization purifying to be purified.Knot Brilliant solvent is using the Conventional solvents in this field, such as methanol, ethyl alcohol, acetonitrile, acetone, ethyl acetate, normal heptane, n-hexane, stone Oily ether or combinations thereof, preferably normal heptane.Crystallization temperature is preferably -20~30 degree, more preferable 20~25 degree.The crystallization purifying Then process is cooled to knot comprising steps of crude product heating (such as to temperature 70-80 degree) is dissolved in recrystallisation solvent first Brilliant temperature, crystallization.
In step (3), the crude product obtained after the reduction reaction is obtained by following steps: reduction reaction knot Shu Hou collects organic phase by reaction mixture after being quenched and extracting；Then organic phase washed, dried and concentrated, obtained To the crude product.
Step (4): in atent solvent, in the presence of a base, compound 4 is subjected to ring closure reaction, to obtain compound 5；
The compound 4 is the change obtained after the crude product crystallization for purifying obtained after reduction reaction in step (3) Close object 4.
In step (4), the alkali can react conventional use of alkali, preferably sodium hydride for such in this field.
In step (4), the molar ratio of alkali and compound 4 is referred to this field and is routinely selected, and preferably 1~10, more It is preferred that 3.
The specific steps of step (4) are as follows: in atent solvent, in the presence of a base, be added dropwise compound 4 solution, then into Row ring closure reaction.The solution of compound 4 can be the DMSO solution of compound 4.The solution of compound 4 is added using dropwise addition mode Add.Time for adding preferably 0.2~1 hour, more preferable 0.5 hour.Dropping temperature is referred to such in this field and reacts normal Rule are selected, and preferably 0~30 degree, more preferable 20~25 degree.
In step (4), preferably 25~100 degree of the reaction temperature of the ring closure reaction, more preferable 80~85 degree.
In step (4), the atent solvent that the ring closure reaction uses routinely is selected referring to this field, preferably THF, DMF, DMSO, more preferable DMSO.
In step (4), the dosage of the atent solvent is referred to this field and is routinely selected.The atent solvent with The volume mass ratio preferably 1~15 of compound 4, more preferable 10.
In step (4), the reaction process of the ring closure reaction can using routine monitoring method in this field (such as TLC, HPLC or NMR) it is monitored, as the terminal of reaction when generally being disappeared using compound 4.The reaction time of the ring closure reaction is preferred 0.5~5 hour.
In step (4), the crude product obtained after ring closure reaction obtains purified compound 5 by crystallization purifying. The solvent that uses is crystallized as the Conventional solvents of this field, as methanol, ethyl alcohol, acetonitrile, acetone, ethyl acetate, normal heptane, just oneself Alkane, petroleum ether or combinations thereof, preferably normal heptane.Preferably -20~30 degree, more preferable 20~25 degree of crystallization temperature.The crystallization is pure The process of change is dissolved in recrystallisation solvent comprising steps of first heating crude product (to temperature 70-80 degree), is then cooled to crystallization Temperature, crystallization.
In step (4), the crude product obtained after the ring closure reaction is obtained by following steps: ring closure reaction knot Shu Hou collects organic phase by reaction mixture after being quenched and extracting；Then organic phase washed, dried and concentrated, obtained To the crude product.
Step (5): in atent solvent, in the presence of hydrogen chloride, compound 5 is carried out to slough chiral auxiliary ((S)-(-)-terf-butylsulfinyl) reaction, to form compound 6；
The compound 5 is the change obtained after the crude product crystallization for purifying obtained after ring closure reaction in step (4) Close object 5.
In step (5), the molar ratio of hydrogen chloride and compound 5 is referred to this field and is routinely selected, preferably 1~ 20, more preferable 5.
In step (5), hydrogen chloride can use solution form or directly adopt gas form.Preferentially use hydrogen chloride solution Form.
In step (5), the hydrogen chloride solution uses dropwise addition mode.Time for adding preferably 0.2~1 hour, more preferably 0.5 hour.Dropping temperature is referred to the routine that such in this field reacts and is selected, and preferably 0~30 degree, more preferable 20~ 25 degree.In the solution, the mass concentration of hydrogen chloride preferably 10%~40%, more preferable 30%.
In step (5), the type of hydrogen chloride solution is selected referring to the routine that such in this field reacts, preferably chlorination Hydrogen dioxane solution, Hydrochloride/ethyl acetate, ethanol solution of hydrogen chloride, hydrogen chloride methanol solution, hydrogen chloride tetrahydro furan It mutters solution；More preferable ethanol solution of hydrogen chloride.
In step (5), the temperature for sloughing chiral auxiliary reaction is preferably 0~60 degree, and more preferable 20~25 degree.
In step (5), the atent solvent for sloughing chiral auxiliary reaction use is routinely selected referring to this field It selects, preferably THF, ether, methyl tertiary butyl ether(MTBE), ethyl acetate or combinations thereof, more preferable methyl tertiary butyl ether(MTBE).
In step (5), the dosage of the atent solvent for sloughing chiral auxiliary reaction is referred to this field routine It is selected, the volume mass ratio preferably 1~15 of the atent solvent and compound 5, more preferable 8.
In step (5), the reaction process for sloughing chiral auxiliary reaction can be using the conventional survey in this field Method for testing (such as TLC, HPLC or NMR) is monitored, as the terminal of reaction when generally being disappeared using compound 5.The reaction Time preferably 0.5~5 hour.
It is described to slough chiral auxiliary after reaction in step (5), reaction mixture is filtered, can be obtained Obtain compound 6.
It further include alkalinization step (6) after the step of above method (5), the alkalinization step includes the following steps: to change It closes object 6 to alkalize, to obtain (S) -3- (4- bromophenyl)-piperidines.
In another preferred example, the alkalinization step includes the following steps: in organic solvent, to be adjusted with alkaline aqueous solution Then the pH of compound 6 collects organic solvent layer, is concentrated to get (S) -3- (4- bromophenyl)-piperidines to alkalinity.
In another preferred example, in step (6), the pH preferably 7~14, more preferable 9~10.
In another preferred example, in step (6), the alkali is sodium hydroxide.The sodium hydroxide can use solution Form or direct solid form.The preferential aqueous solution for using sodium hydroxide.
In another preferred example, the sodium hydrate aqueous solution molar concentration preferably 1~10.
In another preferred example, in step (6), the preferred methylene chloride of organic solvent, dichloroethanes, ethyl acetate, acetic acid The Conventional solvents such as isopropyl ester, toluene, hexamethylene, methyl tertiary butyl ether(MTBE), but not limited to this.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably Example.
Main advantages of the present invention are:
(1) synthetic method of the invention can be prepared by (S) -3- (4- bromophenyl)-piperidine hydrochlorate by the reaction of five steps, should Method has raw material inexpensive and is easy to get, is easy to operate, reaction yield high (yield is up to 52.6%), good product quality (purity and Ee value be all larger than 97.0%), the advantages that by-product is few, be suitable for industrialized production.
(2) synthetic method of the invention is remarkably improved the proportion of products for needing configuration, shape by the method for chiral induction At isomers can obtain by two step recrystallization purifyings, avoid the splitting step and low yield of former technique the problems such as, It is very suitable to industrialized production.
(3) synthetic method of the invention can be using industrial conventional solvent, and reaction temperature can be controlled in 100 DEG C Hereinafter, industrial operation is safe, it is easily controllable.
(4) first step is reacted using solvent free in synthetic method of the invention, non-wastewater discharge, the raw material of recycling It can apply, save the cost is more advantageous to industrialized production.
(5) the present invention also provides what is never reported to be used to prepare in (S) -3- (4- bromophenyl)-piperidines or its salt Intermediate compounds therefor 4.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.The present invention Agents useful for same and raw material are commercially available.
In the application, room temperature refers generally to 10~30 degree.
Embodiment 1
In the three neck round bottom flask of the drying of 100ml put into reactant original -4- bromobenzoic acid trimethyl 1 (41.3g, 150mmol, 1.5eq), then put into raw material (S)-(-)-t-butyl sulfonamide (11.2g, 100mmol, 1.0eq) and catalysis Agent p-methyl benzenesulfonic acid (0.34g, 2mmol, 0.02eq), magnetic agitation.It is small to be heated to 90~95 degree of back flow reactions 3 for temperature in system When, after fully reacting, decompression (0.5mm Hg) steams 75 degree of fractions below, applies for subsequent batches, and remaining system is cooling To room temperature, the crude compound 2 of 49.3g is obtained.Yield 99.0% directly carries out the next step without being further purified.1H NMR (400MHz,CDCl3):δ1.21(9H,s),3.74(3H,s),3.98(2H,dd),7.21-7.23(2H,m),7.42-7.44 (2H,m).
Embodiment 2
In the three neck round bottom flask of the drying of 1000ml put into embodiment 1 obtain crude compound 2 (33.2g, 100mmol, 1.0eq) and reaction dissolvent 250ml anhydrous tetrahydro furan.After nitrogen is replaced 3 times, -70~-65 degree are cooled to, herein At a temperature of be added dropwise 1mol/L LiHMDS solution (200ml, 200mmol, 2eq), dripped off in 1 hour, continue to stir in this temperature Reaction 1 hour.The chloro- 3- iodopropane (26.6g, 130mmol, 1.3eq) of 1-, after 1 hour is added dropwise, -70 is added dropwise in this temperature ~-65 degree stirrings 2 hours.Temperature is heated to -20 degree in subsequent system, and the aqueous ammonium chloride solution of 250ml saturation, dropping temperature is added dropwise Control is in -20~-15 degree.It after being added dropwise, stirs 15 minutes, 100ml ethyl acetate is added and extracts 3 times, merges organic phase, has Machine mutually uses 100ml saturated common salt water washing 1 time.Anhydrous sodium sulfate dries organic phase, filtering.Filtrate decompression is concentrated to dryness, and is obtained yellow 3 crude product (containing compound 3 ') of color oily compounds, drains to obtain 40.1g, yield 100.0%, wherein the purity of compound 3 Greater than 60.0%.
Embodiment 3
In the three neck round bottom flask of the drying of 500ml put into embodiment 2 prepare 3 crude product of compound (compound 3 it is pure 64.0%) (24.9g, 61mmol, 1.0eq) and 160ml tetrahydrofuran are spent, dissolved clarification is stirred.Disposable investment sodium borohydride (7.4g, 195mmol, 5eq) is heated to 60~65 degree of reflux, methanol (12.5g, 390mmol, 10eq) is added dropwise and is catalyzed hydroboration The reduction reaction of sodium adds for about 1 hour, and reaction solution continues back flow reaction 1 hour.It is cooled to room temperature, 200ml unsaturated carbonate is added Hydrogen sodium water solution is added 100ml ethyl acetate and extracts 3 times, combined ethyl acetate phase, 100ml saturated common salt water washing 1 time.Nothing Aqueous sodium persulfate dries organic phase, filtering, and filtrate decompression is concentrated into solvent-free outflow, obtains light yellow oil.Grease is cooling solid Change, 249ml normal heptane be added, is heated to 80 degree of stirring and dissolvings, is cooled to 20~25 degree of crystallizations, filter to obtain 13.7g compound 4, Yield 59%, purity 98.1%.1HNMR(400MHz,CDCl3):δ1.11(9H,s),1.59-1.71(3H,m),1.82-1.91 (1H,m),2.83-2.90(1H,m),3.07-3.10(1H,m),3.17-3.24(1H,m),3.40-3.49(3H,m),7.07- 7.09(2H,m),7.44-7.46(2H,m).
Embodiment 4
Put into the three neck round bottom flask of the drying of 1000ml under nitrogen protection 100ml DMSO and sodium hydride (1.9g, 76mmol, 2.5eq), 20~25 degree of lower 42ml DMSO solutions that compound 4 (11.4g, 30mmol, 1.0eq) is added dropwise.It is heated to It 80~85 degree, is stirred to react 2 hours, is cooled to room temperature, 500ml saturated aqueous ammonium chloride is added and is quenched.60ml acetic acid is added Ethyl ester extracts 3 times, combined ethyl acetate phase, 50ml saturated common salt water washing, and anhydrous sodium sulfate dries, filters, and filtrate decompression is dense It is reduced to dry yellow oil.Normal heptane 100ml is added in grease, is heated to 70 degree of stirring dissolved clarifications, is cooled to 20~25 degree, Insulated and stirred 3 hours, filter to obtain white solid 9.3g, as compound 5.Yield 90%, purity are greater than 98.5%.1H NMR (400MHz,CDCl3):δ1.17(9H,s),1.54-1.82(4H,m),1.97-2.01(1H,m),2.75-2.89(3H,m), 3.43-3.53(2H,m),7.07-7.10(2H,m),7.40-7.43(2H,m).
Embodiment 5
Put into the three neck round bottom flask of the drying of 500ml 147ml methyl tertiary butyl ether(MTBE) and compound 5 (8.6g, 25mmol, 1eq), stir dissolved clarification.30% ethanol solution of hydrogen chloride (20.7g, 250mmol, 10eq) is dripped in half an hour, After being added dropwise, stirs 1 hour, filter to obtain white solid 6.9g, the as (salt of (S) -3- (4- bromophenyl)-piperidines of compound 6 Hydrochlorate).Yield 100%, ee value 97.5%.
1H NMR(400MHz,CDCl3):δ1.59-1.67(1H,m),1.98-2.16(3H,m),2.82-2.91(2H,m), 3.19-3.27(1H,m),3.49-3.56(2H,m),7.06-7.08(2H,m),7.43-7.45(2H,m),9.65(1H,br s),9.86(1H,br s).
Embodiment 6
The three neck round bottom flask for preparing the drying of a 250ml, the investment 104ml methylene chloride in reaction flask, 10ml water, It puts into compound 6 (6.9g, 25mmol, 1eq), the sodium hydrate aqueous solution (about 26ml) that 1mol/L is added dropwise in room temperature adjusts pH=9- 10, reaction solution dissolved clarification.It after being added dropwise, stirs 0.5 hour, branch vibration layer, the washing of 20ml saturated sodium-chloride water solution is added, point Water layer is removed, anhydrous sodium sulfate dries, filters, and white solid 6.0g, yield 100% is concentrated under reduced pressure to obtain, and ee value 97.5% is as changed Close object (S) -3- (4- bromophenyl)-piperidines.
The invention discloses (S) -3- (4- bromophenyl)-piperidine hydrochlorate chiral induction synthetic methods, first by former 4- Bromo-acid trimethyl and the condensation of chiral shift reagent (S)-(+)-t-butyl sulfonamide generate (S)-N- tert-butyl sulfenyl Base -2- phenyl imido is coupled for methyl acetate, then with the chloro- 3- iodopropane of 1-, and obtaining dr by the induction of chiral radicals is about 7:3 Product.The product can be restored without further purification and directly, reduzate only pass through recrystallization can isolated purity exist 90.0% or more diastereoisomer (S)-N- ((S) -2- (4- bromophenyl) -5- chlorine amyl) -2- methylpropane -2- sulfenyl Amine.(S) -3- (4- bromophenyl) -1- ((S)-terf-butylsulfinyl) piperidines is obtained by cyclization reaction again, only passes through recrystallization It can diastereoisomer of the isolated purity 98.5% or more.Chiral induction base is sloughed finally by hydrogen chloride solution Group is greater than 97.0% to get (S) -3- (4- bromophenyl)-piperidine hydrochlorate, ee value.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. the synthetic method of one kind (S) -3- (4- bromophenyl)-piperidines or its salt, comprising steps of
(1) under solvent-free conditions, in the presence of a catalyst, compound 1 is condensed with (S)-(-)-t-butyl sulfonamide Reaction, after reaction, reaction mixture is concentrated, and collects concentrate, to obtain compound 2 or contain compound 2 Product；
(2) in atent solvent, in the presence of a base, the compound 2 that step (1) is obtained or product and 1- containing compound 2 Chloro- 3- iodopropane carries out substitution reaction, to obtain compound 3 or the product containing compound 3；
(3) in atent solvent, in the presence of reducing agent and catalyst, by compound 3 that step (2) obtains or contain compound 3 product carries out reduction reaction, to obtain compound 4；
(4) in atent solvent, in the presence of a base, compound 4 is subjected to ring closure reaction, to obtain compound 5；
(5) in atent solvent, in the presence of hydrogen chloride, compound 5 is carried out to slough chiral auxiliary reaction, to obtain Compound 6；
2. synthetic method as described in claim 1, which is characterized in that further include alkalinization step after the step (5): will Compound 6 alkalizes, to obtain (S) -3- (4- bromophenyl)-piperidines.
3. synthetic method as described in claim 1, which is characterized in that the compound 3 or contain compound 3 that step (2) obtains Product in contain compound 3 '；
4. synthetic method as described in claim 1, which is characterized in that the compound 3 or contain compound 3 that step (2) obtains Product be obtained crude product after substitution reaction, which is directly used in subsequent reactions.
5. synthetic method as described in claim 1, which is characterized in that the compound 4 that step (3) obtains terminates for reduction reaction The product that the crude product obtained afterwards obtains after crystallization purifying.
6. synthetic method as described in claim 1, which is characterized in that the compound 5 that step (4) obtains terminates for ring closure reaction The product that the crude product obtained afterwards obtains after crystallization purifying.
7. such as synthetic method described in claim 5 or 6, which is characterized in that the solvent for crystallizing use is selected from the group: methanol, second Alcohol, acetonitrile, acetone, ethyl acetate, normal heptane, n-hexane, petroleum ether or combinations thereof.
8. such as synthetic method described in claim 5 or 6, which is characterized in that crystallize the temperature used as -20~30 degree.
9. being used to prepare (S) -3- (4- bromophenyl)-piperidines or the midbody compound 4 of its salt；
10. being used to prepare the preparation method of (S) -3- (4- bromophenyl)-piperidines or the midbody compound 4 of its salt, feature exists In, comprising steps of
(1) under solvent-free conditions, in the presence of a catalyst, compound 1 is condensed with (S)-(-)-t-butyl sulfonamide Reaction, after reaction, reaction mixture is concentrated, and collects concentrate, to obtain compound 2 or contain compound 2 Product；
(2) in atent solvent, in the presence of a base, the compound 2 that step (1) is obtained or product and 1- containing compound 2 Chloro- 3- iodopropane carries out substitution reaction, to obtain compound 3 or the product containing compound 3；
(3) in atent solvent, in the presence of reducing agent and catalyst, by compound 3 that step (2) obtains or contain compound 3 product carries out reduction reaction, to obtain compound 4；
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110698388A (en) * 2019-11-01 2020-01-17 暨明医药科技（苏州）有限公司 Method for industrially producing (S) -3- (4-bromophenyl) piperidine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103263A2 (en) * 2010-02-19 2011-08-25 Novartis Ag Process for synthesis of 2-substituted pyrrolidines and piperadines
WO2017181117A1 (en) * 2016-04-15 2017-10-19 Blueprint Medicines Corporation Inhibitors of activin receptor-like kinase
CN108409638A (en) * 2018-05-18 2018-08-17 东南大学 A kind of Niraparib intermediates（S）-3-（4- bromophenyls）The preparation method of piperidines
CN108997313A (en) * 2018-07-09 2018-12-14 常州制药厂有限公司 PARP inhibitor key intermediate and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103263A2 (en) * 2010-02-19 2011-08-25 Novartis Ag Process for synthesis of 2-substituted pyrrolidines and piperadines
WO2017181117A1 (en) * 2016-04-15 2017-10-19 Blueprint Medicines Corporation Inhibitors of activin receptor-like kinase
CN108409638A (en) * 2018-05-18 2018-08-17 东南大学 A kind of Niraparib intermediates（S）-3-（4- bromophenyls）The preparation method of piperidines
CN108997313A (en) * 2018-07-09 2018-12-14 常州制药厂有限公司 PARP inhibitor key intermediate and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FILIP COLPAERT等: "Asymmetric Synthesis of Chiral N-Sulfinyl 3-Alkyl- and 3-Arylpiperidines by r-Alkylation of N-Sulfinyl Imidates with 1-Chloro-3-iodopropane", 《J. ORG. CHEM.》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110698388A (en) * 2019-11-01 2020-01-17 暨明医药科技（苏州）有限公司 Method for industrially producing (S) -3- (4-bromophenyl) piperidine

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