CN109456253B - Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction - Google Patents
Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction Download PDFInfo
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- CN109456253B CN109456253B CN201910026141.3A CN201910026141A CN109456253B CN 109456253 B CN109456253 B CN 109456253B CN 201910026141 A CN201910026141 A CN 201910026141A CN 109456253 B CN109456253 B CN 109456253B
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- 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 invention relates to a method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salts thereof by chiral induction. Specifically, the method of the invention uses trimethyl ortho-4-bromobenzoate and (S) - (-) -tertiary butyl sulfinamide as starting materials, and the (S) -3- (4-bromophenyl) -piperidine or the salt thereof can be obtained after the reactions of condensation, substitution, reduction, ring closing, chiral induction group removal and the like are sequentially carried out. Wherein, after the reduction reaction, a single diastereoisomer with high purity can be obtained by recrystallization. The single diastereoisomer with high purity can be further obtained by recrystallization after the ring closing reaction. The method has the advantages of cheap and easily-obtained raw materials, simple operation, high yield and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salts thereof through chiral induction.
Background
With changes in human living environment, living standards, and lifestyle, as well as advances in medicine, the spectrum of disease has changed dramatically. Infectious diseases in general are increasingly controlled, and cancer is becoming one of the important diseases that are increasingly common and seriously threaten human life and quality of life. Cancer has now become the second leading cause of human death in china and even worldwide. In recent years, the nature of tumors has been elucidated in molecular oncology and molecular pharmacology, and malignant tumors are diseases in which the cells of the body themselves have become uncontrollably proliferated and spread, and are a class of diseases in which the proliferation and differentiation of cells are abnormal.
Nilaparib (Niraparib, 2- [4- ((3S) -3-piperidyl) phenyl ] -2H-indazole-7-formamide, shown as the following formula) belongs to a PARP inhibitor, is a targeted drug for a PARP gene, is mainly used for patients with BRCA1/2 gene mutation, has a definite target point, accords with accurate medical treatment of cancer, and can be used as a second PARP inhibitor on the market when the indication of the pre-submission of Nilaparib is ovarian cancer and breast cancer related to BRCA gene mutation. In the last year, aspirin has marketed the PARP inhibitor Olaparib (Olaparib, also known as Lynparza), which is approved for BRCA-mutated ovarian cancer because of its significant efficacy, with peak sales projected to be over $ 20 billion per year.
At present, the method for synthesizing the nilapanib mainly takes 4- (3S) -3-piperidyl-aniline as a raw material. For example, the following synthetic routes are reported in j.med.chem.2009,52, 7170-:
although this route has a short synthetic route, it has significant disadvantages. Firstly, the starting materials of 4-iodonitrobenzene and 3-pyridine boric acid are expensive and are not easy to obtain in large quantities; secondly, expensive catalysts such as triphenylphosphine palladium, platinum oxide and the like are used in the route, the hydrogenation pressure is high, and industrialization is difficult to realize; thirdly, chemical resolution is used in the route to obtain a single enantiomer, and three times of recrystallization are needed to obtain a qualified enantiomer, so that the efficiency is very low; in addition, sodium azide which is very explosive is used in the route, and the reaction temperature of the step is higher, so that the operation danger is very high.
In 2014, a great improvement was proposed in the synthesis route in org. process res.dev.2014,18, 215-:
the intermediate (S) -3- (4-bromophenyl) -piperidine is used for synthesis of the nilapanib for the first time, sodium azide is avoided, but the synthesis step of the route is long, and various technical problems (such as large raw material consumption, complex operation, large generation of three wastes and the like) are solved.
Disclosure of Invention
In view of the shortcomings in the prior art, the invention aims to provide a novel synthesis method of (S) -3- (4-bromophenyl) -piperidine or salts thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides a method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salts thereof, which comprises the following steps:
(1) under the condition of no solvent and in the presence of a catalyst, carrying out condensation reaction on the compound 1 and (S) - (-) -tert-butyl sulfenamide, after the reaction is finished, concentrating the reaction mixture, and collecting the concentrate to obtain a compound 2 or a product containing the compound 2;
(2) carrying out substitution reaction on the compound 2 or the product containing the compound 2 obtained in the step (1) and 1-chloro-3-iodopropane in an inert solvent in the presence of alkali to obtain a compound 3 or a product containing the compound 3;
(3) carrying out reduction reaction on the compound 3 obtained in the step (2) or a product containing the compound 3 in an inert solvent in the presence of a reducing agent and a catalyst to obtain a compound 4;
(4) subjecting compound 4 to a ring closure reaction in an inert solvent in the presence of a base to obtain compound 5;
(5) in an inert solvent, in the presence of hydrogen chloride, carrying out a chiral induction group removal reaction on the compound 5 to obtain a compound 6;
in another preferred example, after the step (5), an alkalization step is further included: basification of compound 6 gave (S) -3- (4-bromophenyl) -piperidine.
In another preferred example, in the step (1), the concentration condition is that the pressure is 0.5mm Hg and/or the temperature is 60-100 ℃.
In another preferred embodiment, in step (1), the catalyst may be p-toluenesulfonic acid.
In another preferred embodiment, in the step (1), the molar ratio of the catalyst to the compound 1 is 0.01 to 0.10, preferably 0.02.
In another preferred embodiment, the molar ratio of (S) - (-) -tert-butylsulfinamide to compound 1 in step (1) is 0.5 to 3.0, preferably 0.8.
In another preferred example, in the step (1), the reaction temperature of the condensation reaction is 70 to 120 degrees, preferably 95 to 100 degrees.
In another preferred embodiment, the compound 3 or the product containing the compound 3 obtained in the step (2) contains a compound 3';
in another preferred embodiment, the compound 3 or the product containing the compound 3 obtained in the step (2) contains a compound 3'; wherein, the purity of the compound 3 is over 60 percent; preferably, the purity of the compound 3 is 60 to 70 percent.
In another preferred example, in the step (2), the base is LiHMDS or KHMDS.
In another preferred embodiment, in the step (2), the molar ratio of the base to the compound 2 is 1.0 to 4.0, preferably 2.0.
In another preferred embodiment, in the step (2), the molar ratio of the 1-chloro-3-iodopropane to the compound 2 is 0.8 to 2.0, preferably 1.3.
In another preferred example, in the step (2), the reaction temperature of the substitution reaction is-78 to 0 ℃, preferably-70 to-65 ℃.
In another preferred example, the compound 3 or the product containing the compound 3 obtained in the step (2) is a crude product obtained after the substitution reaction is finished, and the crude product is directly used for the subsequent reaction.
In another preferred embodiment, the crude product obtained after the substitution reaction is finished is obtained by the following steps: after the substitution reaction is finished, quenching and extracting the reaction mixture, and collecting an organic phase; and then washing, drying and concentrating the organic phase to obtain the crude product.
In another preferred embodiment, the quenching is carried out using an aqueous ammonium chloride solution.
In another preferred example, the extraction is performed by using ethyl acetate.
In another preferred example, the water washing is performed by using a saturated brine washing.
In another preferred example, the compound 4 obtained in step (3) is a crude product obtained after the reduction reaction is finished and is obtained after crystallization and purification.
In another preferred example, the purity of the compound 4 obtained in the product obtained after crystallization and purification is more than or equal to 90%.
In another preferred example, the crude product obtained after the reduction reaction is finished is obtained by the following steps: after the reduction reaction is finished, quenching and extracting the reaction mixture, and collecting an organic phase; the organic phase is then washed with water, dried and concentrated to give the crude product.
In another preferred embodiment, the quenching is carried out using a saturated aqueous solution of sodium bicarbonate.
In another preferred example, the extraction is performed by using ethyl acetate.
In another preferred example, the water washing is performed by using a saturated brine washing.
In another preferred embodiment, the solvent used for crystallization is selected from the group consisting of: methanol, ethanol, acetonitrile, acetone, ethyl acetate, n-heptane, n-hexane, petroleum ether, or combinations thereof.
In another preferred embodiment, the solvent used for crystallization is n-heptane.
In another preferred embodiment, the temperature for crystallization is-20 to 30 ℃.
In another preferred embodiment, the temperature for crystallization is 20 to 25 ℃.
In another preferred example, in the step (3), the reducing agent is sodium borohydride.
In another preferred embodiment, in the step (3), the molar ratio of the reducing agent to the compound 3 is 1 to 10, preferably 5.
In another preferred example, in step (3), the catalyst is methanol.
In another preferred example, in the step (3), the temperature of the reduction reaction is 25 to 70 degrees, preferably 65 to 70 degrees.
In another preferred example, the compound 5 obtained in step (4) is a product obtained by crystallizing and purifying a crude product obtained after the ring closing reaction is finished.
In another preferred example, the purity of the compound 5 obtained in the product obtained after crystallization and purification is more than or equal to 98%.
In another preferred embodiment, the crude product obtained after the end of the ring closure reaction is obtained by the following steps: after the ring closing reaction is finished, quenching and extracting the reaction mixture, and collecting an organic phase; the organic phase is then washed with water, dried and concentrated to give the crude product.
In another preferred embodiment, the quenching is carried out using an aqueous ammonium chloride solution.
In another preferred example, the extraction is performed by using ethyl acetate.
In another preferred example, the water washing is performed by using a saturated brine washing.
In another preferred embodiment, the solvent used for crystallization is selected from the group consisting of: methanol, ethanol, acetonitrile, acetone, ethyl acetate, n-heptane, n-hexane, petroleum ether, or combinations thereof.
In another preferred embodiment, the solvent used for crystallization is n-heptane.
In another preferred embodiment, the temperature for crystallization is-20 to 30 ℃.
In another preferred embodiment, the temperature for crystallization is 20 to 25 ℃.
In another preferred example, in the step (4), the base is sodium hydride.
In another preferred embodiment, in the step (4), the molar ratio of the base to the compound 4 is 1 to 10, preferably 3.
In another preferred embodiment, in the step (4), the temperature of the ring closing reaction is 25 to 100 degrees, preferably 80 to 85 degrees.
In another preferred embodiment, in the step (5), the molar ratio of the hydrogen chloride to the compound 5 is 1 to 20, preferably 5.
In another preferred example, in the step (5), the hydrogen chloride is in the form of a hydrogen chloride solution.
In another preferred example, in the step (5), the mass concentration of the hydrogen chloride in the solution is 10% to 40%, preferably 30%.
In another preferred example, in the step (5), the hydrogen chloride solution is hydrogen chloride dioxane solution, hydrogen chloride ethyl acetate solution, hydrogen chloride ethanol solution, hydrogen chloride methanol solution or hydrogen chloride tetrahydrofuran solution; preferably a solution of ethanolic hydrogen chloride.
In another preferred embodiment, in the step (5), after the chiral induction group removal reaction is finished, the reaction mixture is filtered to directly obtain the compound 6.
The present invention also provides an intermediate compound 4 useful for the preparation of (S) -3- (4-bromophenyl) -piperidine or a salt thereof;
the present invention also provides a process for the preparation of intermediate compound 4 useful for the preparation of (S) -3- (4-bromophenyl) -piperidine or a salt thereof, comprising the steps of:
(1) under the condition of no solvent and in the presence of a catalyst, carrying out condensation reaction on the compound 1 and (S) - (-) -tert-butyl sulfenamide, after the reaction is finished, concentrating the reaction mixture, and collecting the concentrate to obtain a compound 2 or a product containing the compound 2;
(2) carrying out substitution reaction on the compound 2 or the product containing the compound 2 obtained in the step (1) and 1-chloro-3-iodopropane in an inert solvent in the presence of alkali to obtain a compound 3 or a product containing the compound 3;
(3) carrying out reduction reaction on the compound 3 obtained in the step (2) or a product containing the compound 3 in an inert solvent in the presence of a reducing agent and a catalyst to obtain a compound 4;
it is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have made extensive and intensive studies and have unexpectedly found a method for synthesizing (S) -3- (4-bromophenyl) -piperidine or a salt thereof by chiral induction. On the basis of this, the present invention has been completed.
Compared with the (S) -3- (4-aminophenyl) -piperidine which is the earliest used intermediate in the prior art, the novel bromine fragment intermediate (S) -3- (4-bromophenyl) -piperidine of the nilapanib synthesized by the invention has incomparable advantages and is the most potential intermediate for synthesizing the nilapanib. The intermediate (S) -3- (4-bromophenyl) -piperidine is adopted, so that the defects of high raw material and catalyst cost in the original preparation process can be overcome, and the high-pressure hydrogenation and the use of high-explosive sodium azide are avoided, thereby reducing the requirements on industrial production equipment, safety and the like.
In the existing method, an enzyme catalysis synthesis method is adopted for preparing (S) -3- (4-bromophenyl) -piperidine, but the method has the disadvantages of long synthesis steps, large raw material consumption, extremely complicated and complex operation, and thus, a large amount of three wastes are generated. The invention adopts a chiral induction synthesis method to prepare (S) -3- (4-bromophenyl) -piperidine, and the method has greater advantages than the enzyme catalysis synthesis method adopted by the prior method. The invention provides a method for synthesizing (S) -3- (4-bromophenyl) -piperidine by using a chiral induction reagent, which can form differential diastereoisomers and overcome the problems of low efficiency of chemical resolution and the like.
In the (S) -3- (4-bromophenyl) -piperidine or the salt thereof, the salt is hydrochloride.
The present invention provides a process for producing (S) -3- (4-bromophenyl) -piperidine or a salt thereof, which comprises the following steps (1) to (6).
Step (1): under the condition of no solvent and in the presence of a catalyst, carrying out condensation reaction on the compound 1 and (S) - (-) -tert-butyl sulfenamide, after the reaction is finished, concentrating the reaction mixture, and collecting the concentrate to obtain a compound 2 or a product containing the compound 2;
in step (1), the concentration is generally performed to remove unreacted by-product (methanol) and recover the starting compound 1 (trimethyl ortho-4-bromobenzoate). The concentration is preferably a concentration under reduced pressure. The pressure for the concentration under reduced pressure is preferably 0.5mm Hg. The concentration temperature is preferably 60 to 100 degrees, more preferably 70 to 75 degrees.
In the step (1), the condensation reaction is a solvent-free reaction.
In step (1), the catalyst may be a catalyst conventionally used in such reactions in the art, and is preferably p-toluenesulfonic acid. The catalyst is generally used in an amount that can catalyze such reactions. The molar ratio of the catalyst to the compound 1 is preferably 0.01 to 0.10, more preferably 0.02.
The molar ratio of (S) - (-) -tert-butylsulfinamide to compound 1 in step (1) may be selected according to the conventional practice in the art, preferably 0.5 to 3.0, more preferably 0.8.
In the step (1), the reaction temperature of the condensation reaction can be selected according to the conventional reaction in the field, and is preferably 70-120 ℃, and more preferably 95-100 ℃.
In step (1), the progress of the condensation reaction can be monitored by conventional methods of art (e.g., TLC, HPLC or NMR), and is generally at the end of the reaction when the compound (S) - (-) -tert-butylsulfinamide has disappeared. The time of the condensation reaction is preferably 2 to 6 hours.
Step (2): carrying out substitution reaction on the compound 2 or the product containing the compound 2 obtained in the step (1) and 1-chloro-3-iodopropane in an inert solvent in the presence of alkali to obtain a compound 3 or a product containing the compound 3;
the compound 2 or the product containing the compound 2 obtained in the step (1) is the concentrate collected in the step (1).
The compound 3 or the product containing the compound 3 obtained in the step (2) contains a compound 3'. Wherein, the purity of the compound 3 is over 60 percent; preferably, the purity of the compound 3 is 60 to 70 percent.
In step (2), the base may be a base conventionally used in this type of reaction in the art, preferably LiHMDS.
In the step (2), the molar ratio of the base to the compound 2 can be selected according to the conventional methods in the field, and is preferably 1.0-4.0, more preferably 2.0.
In the step (2), the molar ratio of 1-chloro-3-iodopropane to the compound 2 may be selected in accordance with the conventional practice in the art, and is preferably 0.8 to 2.0, more preferably 1.3.
In the step (2), the reaction temperature of the substitution reaction can be selected according to the conventional procedures of the reactions in the field, preferably-78-0 ℃, and more preferably-70-65 ℃.
In step (2), the inert solvent used in the substitution reaction may be an organic solvent conventionally used in the art for such a reaction, preferably THF.
In the step (2), the volume-to-mass ratio of the inert solvent to the compound 2 can be conventional in the reaction in the field, and is preferably 5-15, and more preferably 10.
In step (2), the concentrate obtained in step (1) is generally cooled to a reaction temperature (e.g., -65 ℃ C.), and then 1-chloro-3-iodopropane is added dropwise. The dropping time of the 1-chloro-3-iodopropane is preferably 0.5 to 2 hours, and more preferably 1 hour.
In step (2), the progress of the substitution reaction can be monitored by conventional methods of art (e.g., TLC, HPLC or NMR), typically by the end of the reaction when compound 2 is eliminated. The time of the substitution reaction is preferably 2 to 10 hours, and more preferably 2 hours.
In the step (2), the crude product obtained after the substitution reaction is finished is purified by column chromatography and then is used for the subsequent reaction or is directly used for the subsequent reaction.
In the step (2), the crude product obtained after the substitution reaction is finished is obtained through the following steps: after the substitution reaction is finished, quenching and extracting the reaction mixture, and collecting an organic phase; then, the organic phase is washed with water, dried and concentrated to obtain a crude product.
And (3): carrying out reduction reaction on the compound 3 obtained in the step (2) or a product containing the compound 3 in an inert solvent in the presence of a reducing agent and a catalyst to obtain a compound 4;
and (3) the compound 3 or the product containing the compound 3 obtained in the step (2) is a crude product obtained after the substitution reaction in the step (2) is finished.
In step (3), the reducing agent may be a reducing agent conventionally used in this type of reaction in the art, and is preferably sodium borohydride.
In the step (3), the molar ratio of the reducing agent to the compound 3 can be selected according to the conventional methods in the art, and is preferably 1 to 10, and more preferably 5. The reducing agent may be added in one portion.
In the step (3), the reaction temperature of the reduction reaction is preferably 25 to 70 degrees, and more preferably 65 to 70 degrees.
In step (3), the inert solvent used for the reduction reaction is selected according to the conventional method in the field, preferably THF, DMF, DCM, more preferably THF. The volume mass ratio of the inert solvent to the compound 3 can be performed according to the conventional method in the field, and is preferably 1-10, and more preferably 8.
In step (3), the progress of the reduction reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), typically ending when compound 3 disappears. The reaction time of the reduction reaction is preferably 0.5 to 5 hours.
In the step (3), the catalyst is methanol. Methanol is added dropwise. The dropping time is preferably 0.2 to 1 hour, more preferably 0.5 hour. The dropping temperature can be selected according to the conventional method of the reaction in the field, preferably 0-30 degrees, more preferably 20-25 degrees.
In the step (3), the crude product obtained after the reduction reaction is finished is purified by crystallization to obtain a purified compound 4. The crystallization solvent employs a solvent conventional in the art, such as methanol, ethanol, acetonitrile, acetone, ethyl acetate, n-heptane, n-hexane, petroleum ether, or a combination thereof, preferably n-heptane. The crystallization temperature is preferably-20 to 30 degrees, more preferably 20 to 25 degrees. The crystallization purification process comprises the following steps: the crude product is first heated (e.g. to a temperature of 70-80 ℃) to dissolve in a crystallization solvent, and then cooled to a crystallization temperature to crystallize.
In the step (3), the crude product obtained after the reduction reaction is finished is obtained through the following steps: after the reduction reaction is finished, quenching and extracting the reaction mixture, and collecting an organic phase; the organic phase is then washed with water, dried and concentrated to give the crude product.
And (4): subjecting compound 4 to a ring closure reaction in an inert solvent in the presence of a base to obtain compound 5;
and the compound 4 is obtained by crystallizing and purifying a crude product obtained after the reduction reaction in the step (3).
In step (4), the base may be a base conventionally used in this type of reaction in the art, and is preferably sodium hydride.
In the step (4), the molar ratio of the base to the compound 4 can be selected according to the conventional methods in the art, and is preferably 1 to 10, more preferably 3.
The specific steps of the step (4) are as follows: in an inert solvent, a solution of compound 4 is added dropwise in the presence of a base, followed by a ring closure reaction. The solution of compound 4 can be a DMSO solution of compound 4. The solution of compound 4 was added dropwise. The dropping time is preferably 0.2 to 1 hour, more preferably 0.5 hour. The dropping temperature can be selected according to the conventional method of the reaction in the field, preferably 0-30 degrees, more preferably 20-25 degrees.
In the step (4), the reaction temperature of the ring closing reaction is preferably 25-100 ℃, and more preferably 80-85 ℃.
In step (4), the inert solvent used for the ring closure reaction is selected according to the routine art, preferably THF, DMF, DMSO, more preferably DMSO.
In step (4), the amount of the inert solvent may be selected according to the conventional art. The volume-mass ratio of the inert solvent to the compound 4 is preferably 1-15, and more preferably 10.
In step (4), the progress of the reaction of the ring closure reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), typically by the end point of the reaction when compound 4 disappears. The reaction time of the ring closure reaction is preferably 0.5 to 5 hours.
In the step (4), the crude product obtained after the ring closing reaction is finished is crystallized and purified to obtain a purified compound 5. The solvent used for crystallization is a solvent conventional in the art, such as methanol, ethanol, acetonitrile, acetone, ethyl acetate, n-heptane, n-hexane, petroleum ether or a combination thereof, preferably n-heptane. The crystallization temperature is preferably-20 to 30 degrees, more preferably 20 to 25 degrees. The crystallization purification process comprises the following steps: firstly, heating (to the temperature of 70-80 ℃) the crude product to dissolve the crude product in a crystallization solvent, then cooling to the crystallization temperature, and crystallizing.
In the step (4), the crude product obtained after the ring closing reaction is finished is obtained through the following steps: after the ring closing reaction is finished, quenching and extracting the reaction mixture, and collecting an organic phase; the organic phase is then washed with water, dried and concentrated to give the crude product.
And (5): subjecting compound 5 to a chirality inducing group removal ((S) - (-) -tert-butylsulfinyl) reaction in the presence of hydrogen chloride in an inert solvent to form compound 6;
and the compound 5 is obtained by crystallizing and purifying a crude product obtained after the ring closing reaction in the step (4).
In the step (5), the molar ratio of the hydrogen chloride to the compound 5 can be selected according to the conventional methods in the field, and is preferably 1 to 20, and more preferably 5.
In step (5), the hydrogen chloride may be in the form of a solution or directly in the form of a gas. Preferably in the form of a hydrogen chloride solution.
In the step (5), the hydrogen chloride solution is dropwise added. The dropping time is preferably 0.2 to 1 hour, more preferably 0.5 hour. The dropping temperature can be selected according to the conventional method of the reaction in the field, preferably 0-30 degrees, more preferably 20-25 degrees. The mass concentration of hydrogen chloride in the solution is preferably 10% to 40%, more preferably 30%.
In the step (5), the kind of the hydrogen chloride solution is selected according to the conventional reaction in the field, and hydrogen chloride dioxane solution, hydrogen chloride ethyl acetate solution, hydrogen chloride ethanol solution, hydrogen chloride methanol solution and hydrogen chloride tetrahydrofuran solution are preferred; more preferably a solution of ethanolic hydrogen chloride.
In the step (5), the temperature for the reaction of removing the chiral induction group is preferably 0-60 ℃, and more preferably 20-25 ℃.
In step (5), the inert solvent used for the chirality-inducing group removal reaction is selected according to the conventional methods in the art, preferably THF, diethyl ether, methyl tert-butyl ether, ethyl acetate or a combination thereof, more preferably methyl tert-butyl ether.
In the step (5), the amount of the inert solvent for removing the chiral induction group reaction can be selected according to the routine in the art, and the volume-to-mass ratio of the inert solvent to the compound 5 is preferably 1-15, and more preferably 8.
In step (5), the progress of the reaction for removing the chirally induced group can be monitored by conventional methods of assay in the art (e.g., TLC, HPLC or NMR), and is generally at the end of the reaction when compound 5 disappears. The reaction time is preferably 0.5 to 5 hours.
In the step (5), after the chiral induction group removal reaction is finished, filtering the reaction mixture to obtain the compound 6.
The method further comprises an alkalization step (6) after the step (5), wherein the alkalization step comprises the following steps: basification of compound 6 gave (S) -3- (4-bromophenyl) -piperidine.
In another preferred example, the alkalizing step includes the steps of: adjusting the pH of the compound 6 to be alkaline with an alkaline aqueous solution in an organic solvent, collecting an organic solvent layer, and concentrating to obtain (S) -3- (4-bromophenyl) -piperidine.
In another preferred example, in the step (6), the pH is preferably 7 to 14, and more preferably 9 to 10.
In another preferred example, in the step (6), the alkali is sodium hydroxide. The sodium hydroxide may be in solution or in direct solid form. Preference is given to using aqueous sodium hydroxide solutions.
In another preferred embodiment, the molar concentration of the sodium hydroxide aqueous solution is preferably 1 to 10.
In another preferred example, in the step (6), the organic solvent is preferably, but not limited to, conventional solvents such as dichloromethane, dichloroethane, ethyl acetate, isopropyl acetate, toluene, cyclohexane, methyl t-butyl ether, and the like.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The main advantages of the invention are:
(1) the synthesis method can prepare the (S) -3- (4-bromophenyl) -piperidine hydrochloride through five-step reaction, has the advantages of low-cost and easily-obtained raw materials, simple and convenient operation, high reaction yield (the yield can reach 52.6%), good product quality (the purity and the ee value are both more than 97.0%), few byproducts and the like, and is suitable for industrial production.
(2) The synthesis method can obviously improve the proportion of products needing configuration by a chiral induction method, and the formed isomer can be obtained by two-step recrystallization purification, thereby avoiding the problems of resolution step, low yield and the like of the prior art and being very suitable for industrial production.
(3) The synthesis method of the invention can adopt the conventional solvent in industry, the reaction temperature can be controlled below 100 ℃, and the industrial operation is safe and easy to control.
(4) The first step of the synthesis method of the invention adopts no solvation reaction and no waste water discharge, and the recovered raw materials can be reused, thus saving the cost and being more beneficial to industrial production.
(5) The present invention also provides an intermediate compound 4 which has never been reported for the preparation of (S) -3- (4-bromophenyl) -piperidine or a salt thereof.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. The reagents and starting materials used in the present invention are commercially available.
In the present application, room temperature generally means 10 to 30 ℃.
Example 1
A100 mL dry three neck round bottom flask was charged with the reactant trimethyl ortho-4-bromobenzoate 1(41.3g,150mmol,1.5eq), followed by the starting material (S) - (-) -tert-butylsulfinamide (11.2g,100mmol,1.0eq) and the catalyst p-toluenesulfonic acid (0.34g,2mmol,0.02 e)q), magnetically stirring. Heating the system to 90-95 ℃ for reflux reaction for 3 hours, after the reaction is completed, distilling the distillate below 75 ℃ under reduced pressure (0.5mm Hg) for reuse in subsequent batches, and cooling the residual system to room temperature to obtain 49.3g of crude compound 2. The yield is 99.0%, and the next reaction is directly carried out without further purification.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).
Example 2
Into a 1000ml dry three necked round bottom flask were charged crude compound 2(33.2g,100mmol,1.0eq) obtained in example 1 and reaction solvent 250ml anhydrous tetrahydrofuran. After 3 times of nitrogen replacement, the mixture is cooled to-70 to-65 ℃, 1mol/L LiHMDS solution (200ml,200mmol,2eq) is dripped at the temperature, the dripping is finished within 1 hour, and the stirring reaction is continued for 1 hour at the temperature. 1-chloro-3-iodopropane (26.6g,130mmol,1.3eq) was added dropwise at this temperature, and after 1 hour of addition, the mixture was stirred at-70 ℃ to-65 ℃ for 2 hours. Then heating the system to-20 ℃, dropwise adding 250ml of saturated ammonium chloride aqueous solution, and controlling the dropwise adding temperature to-20 to-15 ℃. After the addition, the mixture was stirred for 15 minutes, extracted 3 times with 100ml of ethyl acetate, the organic phases were combined and washed 1 time with 100ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate under reduced pressure to dryness to obtain crude yellow oily compound 3 (containing compound 3'), and drying to obtain 40.1g with yield of 100.0%, wherein the purity of compound 3 is more than 60.0%.
Example 3
A500 ml dry three-necked round-bottomed flask was charged with crude compound 3 (64.0% purity of compound 3) prepared in example 2 (24.9g,61mmol,1.0eq) and 160ml tetrahydrofuran, and the mixture was stirred to dissolve. Adding sodium borohydride (7.4g,195mmol,5eq) at one time, heating to 60-65 ℃, refluxing, and dropwise adding methanol (12.5g,390mmol,10 eq)) Catalyzing the reduction reaction of sodium borohydride, completing the addition within about 1 hour, and continuously refluxing the reaction liquid for 1 hour. Cooled to room temperature, 200ml of saturated aqueous sodium bicarbonate solution was added, 100ml of ethyl acetate was added and extracted 3 times, and the ethyl acetate phases were combined and washed 1 time with 100ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no solvent flowed out to give a pale yellow oil. Cooling and solidifying the oily matter, adding 249ml of n-heptane, heating to 80 ℃, stirring and dissolving, cooling to 20-25 ℃, crystallizing, and filtering to obtain 13.7g of compound 4, wherein the yield is 59%, and the purity is 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).
Example 4
100ml of DMSO and sodium hydride (1.9g,76mmol,2.5eq) are placed in a 1000ml dry three-neck round-bottom flask under nitrogen protection, and a solution of compound 4(11.4g,30mmol,1.0eq) in 42ml of DMSO is added dropwise at 20-25 ℃. Heating to 80-85 ℃, stirring for reaction for 2 hours, cooling to room temperature, and adding 500ml of saturated ammonium chloride aqueous solution for quenching. Extracting with 60ml ethyl acetate for 3 times, mixing ethyl acetate phases, washing with 50ml saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance. And adding 100ml of n-heptane into the oily substance, heating to 70 ℃, stirring to be clear, cooling to 20-25 ℃, keeping the temperature, stirring for 3 hours, and filtering to obtain 9.3g of white solid, namely the compound 5. The yield is 90 percent, and the purity is more than 98.5 percent.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).
Example 5
Into a 500ml dry three necked round bottom flask was charged 147ml of methyl tert-butyl ether and compound 5(8.6g,25mmol,1eq) and the solution was stirred to a clear solution. After the completion of the dropwise addition of 30% ethanol hydrogen chloride solution (20.7g,250mmol,10eq) within half an hour, the mixture was stirred for 1 hour and filtered to obtain 6.9g of a white solid, which was hydrochloride of compound 6((S) -3- (4-bromophenyl) -piperidine). The yield thereof was found to be 100%, and the ee value thereof was found to be 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,brs),9.86(1H,br s).
Example 6
A 250ml dry three-neck round-bottom flask was prepared, 104ml dichloromethane and 10ml water were put into a reaction flask, compound 6(6.9g,25mmol,1eq) was put into the flask, 1mol/L aqueous sodium hydroxide solution (about 26ml) was added dropwise at room temperature to adjust pH 9 to 10, and the reaction solution was cleared. After the dropwise addition, the mixture was stirred for 0.5 hour, the aqueous layer was separated, 20ml of a saturated aqueous sodium chloride solution was added thereto, the mixture was washed, the aqueous layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid (6.0 g), the yield was 100%, and the ee value was 97.5%, which was the compound (S) -3- (4-bromophenyl) -piperidine.
The invention discloses a chiral induction synthesis method of (S) -3- (4-bromophenyl) -piperidine hydrochloride, which comprises the steps of firstly condensing original 4-bromophenylacetic acid trimethyl ester and a chiral induction reagent (S) - (+) -tert-butylsulfinamide to generate (S) -N-tert-butylsulfinyl-2-phenylaminoacetic acid methyl ester, then coupling with 1-chloro-3-iodopropane, and obtaining dr which is about 7 through the induction of chiral groups: 3, or a salt thereof. The product can be directly reduced without purification, and the reduced product can be separated to obtain the diastereoisomer (S) -N- ((S) -2- (4-bromophenyl) -5-chloropentyl) -2-methylpropane-2-sulfinamide with the purity of more than 90.0 percent only by recrystallization. Then (S) -3- (4-bromophenyl) -1- ((S) -tert-butylsulfinyl) piperidine is obtained through cyclization reaction, and diastereoisomer with the purity of more than 98.5 percent can be obtained through separation only through recrystallization. And finally, removing the chiral induction group by using a hydrogen chloride solution to obtain the (S) -3- (4-bromophenyl) -piperidine hydrochloride, wherein the ee value is more than 97.0%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (9)
1. A method of synthesizing (S) -3- (4-bromophenyl) -piperidine or a salt thereof, comprising the steps of:
(1) under the condition of no solvent and in the presence of a catalyst, carrying out condensation reaction on the compound 1 and (S) - (-) -tert-butyl sulfenamide, after the reaction is finished, concentrating the reaction mixture, and collecting the concentrate to obtain a compound 2 or a product containing the compound 2; the catalyst is p-toluenesulfonic acid; the molar ratio of catalyst to compound 1 was 0.02;
(2) carrying out substitution reaction on the compound 2 or the product containing the compound 2 obtained in the step (1) and 1-chloro-3-iodopropane in an inert solvent in the presence of alkali to obtain a compound 3 or a product containing the compound 3; the inert solvent is tetrahydrofuran; the base is LiHMDS; the molar ratio of base to compound 2 was 2.0; the molar ratio of 1-chloro-3-iodopropane to compound 2 is 1.3; the temperature of the substitution reaction is-70 to-65 ℃; the substitution reaction time takes the disappearance of the compound 2 as the end point of the reaction;
(3) carrying out reduction reaction on the compound 3 obtained in the step (2) or a product containing the compound 3 in an inert solvent in the presence of a reducing agent and a catalyst to obtain a compound 4; the inert solvent is tetrahydrofuran; the reducing agent is sodium borohydride; the catalyst is methanol; the molar ratio of the reducing agent to the compound 3 is 5; the reduction reaction temperature is 65-70 ℃; the reduction reaction time is the end point of the reaction when the compound 3 disappears;
(4) subjecting compound 4 to a ring closure reaction in an inert solvent in the presence of a base to obtain compound 5; the inert solvent is DMSO; the base is sodium hydride; the ring closing reaction temperature is 80-85 ℃; the ring closing reaction time is the end point of the reaction when the compound 4 disappears;
(5) in an inert solvent, in the presence of hydrogen chloride, carrying out a chiral induction group removal reaction on the compound 5 to obtain a compound 6; the inert solvent is methyl tert-butyl ether; the hydrogen chloride is in the form of a hydrogen chloride solution; the hydrogen chloride solution is hydrogen chloride ethanol solution; the temperature of the reaction for removing the chiral induction group is 0-30 ℃; the time for the reaction of removing the chiral induction group takes the disappearance of the compound 5 as the end point of the reaction;
2. the synthesis method according to claim 1, characterized in that after the step (5), it further comprises an alkalization step: basification of compound 6 gave (S) -3- (4-bromophenyl) -piperidine.
3. The method of claim 1, wherein compound 3 or a product containing compound 3 obtained in step (2) contains compound 3';
4. the method of claim 1, wherein the compound 3 or the product containing the compound 3 obtained in step (2) is a crude product obtained after the completion of the substitution reaction, and the crude product is used directly in the subsequent reaction.
5. The synthesis method according to claim 1, wherein the compound 4 obtained in the step (3) is a crude product obtained after the reduction reaction is completed and is purified by crystallization.
6. The synthesis method according to claim 1, wherein the compound 5 obtained in step (4) is a crude product obtained after the ring closure reaction is finished and is obtained after crystallization and purification.
7. The synthesis process according to claim 5 or 6, characterized in that the crystallization is carried out using a solvent selected from the group consisting of: methanol, ethanol, acetonitrile, acetone, ethyl acetate, n-heptane, n-hexane, petroleum ether, or combinations thereof.
8. The synthesis method according to claim 5 or 6, wherein the crystallization temperature is-20 to 30 ℃.
9. A process for the preparation of intermediate compound 4 for the preparation of (S) -3- (4-bromophenyl) -piperidine or a salt thereof, characterized by the steps of:
(1) under the condition of no solvent and in the presence of a catalyst, carrying out condensation reaction on the compound 1 and (S) - (-) -tert-butyl sulfenamide, after the reaction is finished, concentrating the reaction mixture, and collecting the concentrate to obtain a compound 2 or a product containing the compound 2; the catalyst is p-toluenesulfonic acid; the molar ratio of catalyst to compound 1 was 0.02;
(2) carrying out substitution reaction on the compound 2 or the product containing the compound 2 obtained in the step (1) and 1-chloro-3-iodopropane in an inert solvent in the presence of alkali to obtain a compound 3 or a product containing the compound 3; the inert solvent is tetrahydrofuran; the base is LiHMDS; the molar ratio of base to compound 2 was 2.0; the molar ratio of 1-chloro-3-iodopropane to compound 2 is 1.3; the temperature of the substitution reaction is-70 to-65 ℃; the substitution reaction time takes the disappearance of the compound 2 as the end point of the reaction;
(3) carrying out reduction reaction on the compound 3 obtained in the step (2) or a product containing the compound 3 in an inert solvent in the presence of a reducing agent and a catalyst to obtain a compound 4; the inert solvent is tetrahydrofuran; the reducing agent is sodium borohydride; the catalyst is methanol; the molar ratio of the reducing agent to the compound 3 is 5; the reduction reaction temperature is 65-70 ℃; the reduction reaction time is the end point of the reaction when the compound 3 disappears;
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